Natalie L. Rasgon

Professor of Psychiatry and Behavioral Sciences (General Psychiatry and Psychology-Adult) and, by courtesy, of Obstetrics and Gynecology (Maternal Fetal Medicine) at the Stanford University Medical Center

Bio

Bio

Dr. Rasgon is a Professor in the Department of Psychiatry and Behavioral Sciences and Obstetrics and Gynecology in the Stanford School of Medicine. Dr. Rasgon has been involved in longitudinal placebo-controlled neuroendocrine studies for over two decades, and she has been involved in neuroendocrine and brain imaging studies of estrogen effects on depressed menopausal women for over 10 years. In addition to her duties as a Professor of Psychiatry and Obstetrics & Gynecology, Dr. Rasgon is also the Director of the Stanford Center for Neuroscience in Women?s Health and Associate Dean of Academic Affairs for the School of Medicine. She has an extensive history of teaching and mentoring, and many of her trainees have secured independent faculty positions in academia.

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Research & Scholarship

Current Research and Scholarly Interests

Dr. Rasgon is a Professor in the Department of Psychiatry and Behavioral Sciences and Obstetrics and Gynecology in the Stanford School of Medicine. Before joining Stanford in October 2002, Dr. Rasgon obtained an M.D. from the U.S.S.R. in 1980, a Ph.D. in Reproductive Endocrinology in 1988 from the Central Institute of Postgraduate Medical Education, and a Ph.D. in Pathological Physiology from the Central Research Institute of General Pathology & Pathological Physiology Academy of Medical Sciences, Moscow, USSR. In addition, Dr. Rasgon was an NSRA Research Fellow at the Neuropsychiatric Institute, UCLA School of Medicine from 1995-1996, an Assistant Clinical Professor, Department of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine, Neuropsychiatric Institute and Hospital, and the Director of the UCLA Menopause-Related Mood Disorders Program, UCLA Neuropsychiatric Institute and Hospital.

Dr. Rasgon has been involved in longitudinal placebo-controlled neuroendocrine studies for nearly two decades, and she has been involved in neuroendocrine and brain imaging studies of estrogen effects on depressed menopausal women for the last eight years. It should be noted that in addition to her duties as a Professor of Psychiatry and Obstetrics & Gynecology, Dr. Rasgon is also the Director of the Behavioral Neuroendocrinology Program and the Women's Wellness Program in the Department of Psychiatry. Research in the Behavioral Neuroendocrinology Program, which Dr. Rasgon founded, focuses on the interaction between reproductive hormones and brain function. Research efforts of the lab are concentrated in two areas: (1) the reproductive endocrine status of women with affective disorders, and (2) the neurobiology of the effects of hormone therapy in aging women.

Clinical Trials

Pioglitazone in Patients With Mood DisordersNot Recruiting

The purpose of this study is to see how an insulin sensitizing medication, Pioglitazone, can
cause changes in mood in some depressed patients. Study participants receive assessment of
their cognitive and metabolic functioning.
If they meet criteria, they will be asked to take either Pioglitazone or a placebo for a
90-day trial. Participants will undergo an Oral Glucose Tolerance Test to measure fasting
insulin and glucose levels, as well as routine blood testing.
The investigators hope to quantify the role of Pioglitazone in patients with mood disorders
and compare the values to those previously obtained in a healthy age-matched control
population. The investigators also hope to examine the association between IR and cognitive
performance and clinical course of depression in patients with mood disorders.

Stanford is currently not accepting patients for this trial.For more information, please contact Rachael Lazar, 650-724-4559.

Treatment With Namenda in Women at Risk for Cognitive DeclineNot Recruiting

This research aims to explore the effectiveness of memantine (Namenda) in treating
post-menopausal women between the ages of 50 and 65, who are at risk for cognitive decline.
Memantine has already been shown to offer cognitive benefits to patients suffering from
Alzheimer's disease, but it's potential for treating those at risk for cognitive decline
without Alzheimer's disease or other dementia has yet to be evaluated. It is possible that
memantine may offer neurocognitive benefits to this population, as well. Participants are
asked to take medication for six months, complete neuropsychological testing, and one blood
draw.

Effects of Mifepristone on Biomarkers of Metabolic Function and Neuropsychological Performance Among Middle-Aged and Older IndividualsNot Recruiting

The purpose of this study is to study the effect of cortisol,a stress hormone in the body, on
memory and attention in people with a history of depression, but who are not in the midst of
a current depressive episode.
Cortisol may affect parts of the brain associated with memory and attention directly. It may
also indirectly affect the brain by controlling how much insulin the body makes. Insulin is
thought to impact cognition by changing the amount of sugar available in certain parts of the
brain.
The investigators are studying this question by giving patients a medication, called
Mifepristone, which reduces cortisol's effect on the brain. The investigators will compare
results from several groups of people, including differences between men and women, and
between those with and without insulin resistance.

Stanford is currently not accepting patients for this trial.For more information, please contact Danielle Balzaifore, M.S., 650-736-2182.

Effects of Liraglutide on Hippocampal Structure and Function in Aging Adults With PrediabetesNot Recruiting

The purpose of this study is to evaluate the effects of liraglutide on the memory and
attention of people with insulin resistance. Liraglutide is a medication that makes the body
more sensitive to insulin, and therefore may allow it to manage sugar more effectively.
The investigators are looking specifically at a region of the brain that is associated with
memory and attention, called the hippocampus, in order to see whether treatment this
treatment will change performance on memory and attention tasks. The investigators are also
taking an MRI of the brain to see whether there are changes to the size and shape of the
hippocampus after treatment.
All subjects in this study will be 50-70 years old and have pre- diabetes. Half of all
subjects will have a family history of dementia, while the other half will not.

Stanford is currently not accepting patients for this trial.For more information, please contact Kathleen Watson, 646-245-8434.

Insulin resistance is known to be associated with mood disorders and cognitive difficulties.
The purpose of this study is to treat depressed patients with rosiglitazone (also known as
[AKA] Avandia), therefore improving glucose sensitivity, which in turn has the potential to
affect mood and thinking. We, the researchers at Stanford University, are recruiting men and
women who have been diagnosed with depression, and are willing to participate in this 3 month
study. Participation involves neuropsychological testing, 2 blood draws called an oral
glucose tolerance test (OGTT), which tests for glucose and insulin levels, and the
medication, rosiglitazone. Participants are allowed to continue on their current psychiatric
medication.

Lamotrigine in the Treatment of Bipolar Disorder in Women of Reproductive AgeNot Recruiting

This project will expand current knowledge of reproductive biology in women with bipolar
disorder as well as assessing the impact of lamotrigine use for the treatment of bipolar
disorder on reproductive function. Specifically, this study examines mood over the menstrual
cycle and ovulation for three consecutive menstrual cycles in women treated for bipolar I,
II, or NOS (not otherwise specified) with lamotrigine. In addition, testosterone and lipid
concentrations will be measured before the participant starts receiving lamotrigine, as well
as six months after receiving lamotrigine.

Abstract

Although bipolar disorder (BD) is a common recurrent condition with highly heterogeneous illness course, data are limited regarding clinical implications of interactions between gender and onset age. We assessed relationships between onset age and demographic/illness characteristics among BD patients stratified by gender.Demographic and unfavorable illness characteristics, descriptive traits, and clinical correlates were compared in 502 patients from Stanford University BD Clinic patients enrolled in the Systematic Treatment Enhancement Program for BD between 2000 and 2011, stratified by gender, across pre-, peri-, and post-pubertal (<12, 13-16, and >17 years, respectively) onset-age subgroups.Among 502 BD patients, 58.2% were female, of whom 21.9% had pre-pubertal, 30.7% peri-pubertal, and 47.4% post-pubertal onset. Between genders, although demographics, descriptive characteristics, and most clinical correlates were statistically similar, there were distinctive onset-age related patterns of unfavorable illness characteristics. Among females, rates of 6/8 primary unfavorable illness characteristics were significantly higher in pre-pubertal and peri-pubertal compared to post-pubertal onset patients. However, among males, rates of only 3/8 unfavorable illness characteristics were significantly higher in only pre-pubertal versus post-pubertal onset patients, and none between peri-pubertal versus post-pubertal onset patients.Caucasian, insured, suburban, American specialty clinic-referred sample limits generalizability, onset age based on retrospective recall.We describe different phenotypic presentations across age at illness onset groups according to gender. Among females and males, peri-pubertal and post-pubertal onset age groups were more different and more similar, respectively. Further investigation is warranted to assess implications of gender-by-onset-age interactions to more accurately delineate distinctive BD phenotypes.

Abstract

We studied peripheral leukocyte telomere length (LTL) as a predictor of antidepressant response to PPAR-? agonist in patients with unremitted depression. In addition we examined correlation between LTL and the insulin resistance (IR) status in these subjects. Forty-two medically stable men and women ages 23-71 with non-remitted depression participated in double-blind placebo-controlled add-on of Pioglitazone to treatment-as-usual. Oral glucose tolerance tests were administered at baseline and at 12 weeks. Diagnostic evaluation of psychiatric disorders was performed at baseline and mood severity was followed weekly throughout the duration of the trial. At baseline, no differences in LTL were detected by depression severity, duration or chronicity. LTL was also not significantly different between insulin-resistant and insulin-sensitive subjects at baseline. Subjects with longer telomeres exhibited greater declines in depression severity in the active arm, but not in a placebo arm, P=0.005, r=-0.63, 95% confidence interval (95% CI)=(-0.84,-0.21). In addition, LTL predicted improvement in insulin sensitivity in the group overall and did not differ between intervention arms, P=0.036, r=-0.44, 95% CI=(-0.74,0.02) for the active arm, and P=0.026, r=-0.50, 95% CI=(-0.78,-0.03) for the placebo arm. LTL may emerge as a viable predictor of antidepressant response. An association between insulin sensitization and LTL regardless of the baseline IR status points to potential role of LTL as a non-specific moderator of metabolic improvement in these patients.

Abstract

Previous studies suggest that insulin-sensitizing agents could play a significant role in the treatment of major depression, particularly depression in patients with documented insulin resistance or those who are resistant to standard psychopharmacological approaches. This study aimed to assess the effects on depressive symptoms with adjuvant treatment with the PPAR?-agonist pioglitazone. Patients (N=37) with non-psychotic, non-remitting depression receiving standard psychiatric regimens for depression were randomized across an insulin sensitivity spectrum in a 12-week double blind, randomized controlled trial of pioglitazone or placebo. Improvement in depression was associated with improvement in glucose metabolism but only in patients with insulin resistance. An age effect was also shown in that response to pioglitazone was more beneficial in younger aged patients. Study findings suggest differential improvement in depression severity according to both glucose metabolic status and level of depression at baseline. A greater understanding of the reciprocal links between depression and IR may lead to a dramatic shift in the way in which depression is conceptualized and treated, with a greater focus on treating and/or preventing metabolic dysfunction.

Abstract

Dietary supplements are taken by about half of Americans. Knowledge of dietary supplement use is important because they may interact with prescription drugs or other supplements, cause adverse reactions including psychiatric symptoms, or contain inherently toxic ingredients or contaminants. This study explores the use of dietary supplements by patients with bipolar disorder in the US.Data were obtained from an ongoing, naturalistic study of patients with bipolar disorder who received pharmacological treatment as usual. The patients self-reported their daily mood, sleep, and medications taken, including all drugs prescribed for bipolar disorder or that the patient felt impacted their mood. These included other prescribed drugs, over-the-counter drugs and dietary supplements. Drugs that received premarketing approval from the FDA were not included as dietary supplements. Patient demographics and daily medication use were characterized.Data were available from 348 patients in the US who returned a mean 249.5 days of data. In addition to prescribed psychiatric drugs, 101 of the 348 patients (29 %) used a dietary supplement for at least 7 days and 69 (20 %) used a supplement long term (for at least 50 % of days). Of the 101 supplement users, 72 (71.3 %) took one supplement daily. The 101 patients tried over 40 different supplements, and the long-term users took 19 different supplements. The most commonly taken supplements for both groups were fish oil, B vitamins, melatonin, and multivitamins. Patients using supplements were more likely to be white (p?0.001), older (p?=?0.009), and ill for more years (p?=?0.025).Many patients with bipolar disorder use dietary supplements in addition to prescribed drugs. Physicians should obtain detailed information about all dietary supplements taken by patients with bipolar disorder.

Abstract

Use of estrogen-based hormone therapy (HT) as a protection from cognitive decline and Alzheimer disease (AD) is controversial, although cumulative data support HT use when initiated close to menopause onset with estrogen formulations containing 17?-estradiol preferable to conjugated equine estrogen formulations. Little is known regarding specific populations of women who may derive benefit from HT.Women with heightened risk for AD (aged 49-69), all of whom were taking HT for at least 1 year and most of whom initiated HT close to menopause onset, underwent cognitive assessment followed by randomization to continue or discontinue HT. Assessments were repeated at 2 years after randomization.Women who continued HT performed better on cognitive domains composed of measures of verbal memory and combined attention, working memory, and processing speed measures. Women who used 17?-estradiol versus conjugated equine estrogen, whether randomized to continue or discontinue HT, showed better verbal memory performance at the 2-year follow-up assessment. An interaction was also found with HT randomization and family history of AD in a first-degree relative. All female offspring of patients with AD declined in verbal memory; however, women who continued HT declined less than women who discontinued HT. Women without a first-degree relative with AD showed verbal memory improvement (likely because of practice effects) with continuance and declined with discontinuance of HT.Continuation of HT use appears to protect cognition in women with heightened risk for AD when initiated close to menopause onset.

Abstract

The strengths and limitations of considering childhood-and adolescent-onset bipolar disorder (BD) separately versus together remain to be established. We assessed this issue.BD patients referred to the Stanford Bipolar Disorder Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD Affective Disorders Evaluation. Patients with childhood- and adolescent-onset were compared to those with adult-onset for 7 unfavorable bipolar illness characteristics with replicated associations with early-onset patients.Among 502 BD outpatients, those with childhood- (<13 years, N=110) and adolescent- (13-18 years, N=218) onset had significantly higher rates for 4/7 unfavorable illness characteristics, including lifetime comorbid anxiety disorder, at least ten lifetime mood episodes, lifetime alcohol use disorder, and prior suicide attempt, than those with adult-onset (>18 years, N=174). Childhood- but not adolescent-onset BD patients also had significantly higher rates of first-degree relative with mood disorder, lifetime substance use disorder, and rapid cycling in the prior year. Patients with pooled childhood/adolescent - compared to adult-onset had significantly higher rates for 5/7 of these unfavorable illness characteristics, while patients with childhood- compared to adolescent-onset had significantly higher rates for 4/7 of these unfavorable illness characteristics.Caucasian, insured, suburban, low substance abuse, American specialty clinic-referred sample limits generalizability. Onset age is based on retrospective recall.Childhood- compared to adolescent-onset BD was more robustly related to unfavorable bipolar illness characteristics, so pooling these groups attenuated such relationships. Further study is warranted to determine the extent to which adolescent-onset BD represents an intermediate phenotype between childhood- and adult-onset BD.

Abstract

Environmental conditions early in life may imprint the circadian system and influence response to environmental signals later in life. We previously determined that a large springtime increase in solar insolation at the onset location was associated with a younger age of onset of bipolar disorder, especially with a family history of mood disorders. This study investigated whether the hours of daylight at the birth location affected this association.Data collected previously at 36 collection sites from 23 countries were available for 3896 patients with bipolar I disorder, born between latitudes of 1.4 N and 70.7 N, and 1.2 S and 41.3 S. Hours of daylight variables for the birth location were added to a base model to assess the relation between the age of onset and solar insolation.More hours of daylight at the birth location during early life was associated with an older age of onset, suggesting reduced vulnerability to the future circadian challenge of the springtime increase in solar insolation at the onset location. Addition of the minimum of the average monthly hours of daylight during the first 3 months of life improved the base model, with a significant positive relationship to age of onset. Coefficients for all other variables remained stable, significant and consistent with the base model.Light exposure during early life may have important consequences for those who are susceptible to bipolar disorder, especially at latitudes with little natural light in winter. This study indirectly supports the concept that early life exposure to light may affect the long term adaptability to respond to a circadian challenge later in life.

Abstract

The transition to motherhood is a time of elevated risk for clinical depression. Dispositional optimism may be protective against depressive symptoms; however, the arrival of a newborn presents numerous challenges that may be at odds with initially positive expectations, and which may contribute to depressed mood. We have explored the relative contributions of antenatal and postnatal optimism regarding maternity to depressive symptoms in the postnatal period. Ninety-eight pregnant women underwent clinician interview in the third trimester to record psychiatric history, antenatal depressive symptoms, and administer a novel measure of optimism towards maternity. Measures of depressive symptoms, attitudes to maternity, and mother-to-infant bonding were obtained from 97 study completers at monthly intervals through 3 months postpartum. We found a positive effect of antenatal optimism, and a negative effect of postnatal disconfirmation of expectations, on depressive mood postnatally. Postnatal disconfirmation, but not antenatal optimism, was associated with more negative attitudes toward maternity postnatally. Antenatal optimism, but not postnatal disconfirmation, was associated with reduced scores on a mother-to-infant bonding measure. The relationships between antenatal optimism, postnatal disconfirmation of expectations, and postnatal depression held true among primigravidas and multigravidas, as well as among women with prior histories of mood disorders, although antenatal optimism tended to be lower among women with mental health histories. We conclude that cautious antenatal optimism, rather than immoderate optimism or frank pessimism, is the approach that is most protective against postnatal depressive symptoms, and that this is true irrespective of either mood disorder history or parity. Factors predisposing to negative cognitive assessments and impaired mother-to-infant bonding may be substantially different than those associated with depressive symptoms, a finding that merits further study.

Abstract

To examine the occurrence of menstrually-entrained mood cycling in women with treated bipolar disorder as compared to healthy controls, and to explore whether there is a specific effect of lamotrigine in dampening menstrually-entrained cyclicity of mood.Observational comparison study of daily self-ratings of mood, sleep, and insomnia obtained over a mean of four menstrual cycles in 42 women with bipolar disorder taking lamotrigine as part of their treatment, 30 women with bipolar disorder receiving mood stabilizing regimens without lamotrigine, and 13 healthy controls, all with physiological menstrual cycles. Additional exploratory analysis of interactions between psychopharmacological regimen and hormonal contraceptive use in the group of women with bipolar disorder, with the addition of 19 women with bipolar disorder who were using hormonal contraceptives.Women treated for bipolar disorder manifested lower average mood, longer average nightly sleep duration, and greater fluctuations in mood and sleep across menstrual cycle phases than healthy controls. Women with bipolar disorder who were taking lamotrigine had less fluctuation in mood both within and across menstrual cycle phases, and were more similar to the control group than to women with bipolar disorder who were not taking lamotrigine in this respect. In addition, medications with GABA-A receptor modulating effects were found to result in improved mood ratings when combined with hormonal contraceptives.Menstrually-entrained mood fluctuation is present in women treated for bipolar disorder to a greater degree than in healthy controls. Lamotrigine may be of use in mitigating this fluctuation. GABA-A receptor modulators in general may act synergistically with hormonal contraceptives to enhance mood in women with bipolar disorder; this hypothesis merits further study.

Abstract

To test our hypothesis that pre-treatment executive function and brain regional activation during executive function would discriminate between responders and non-responders to cognitive behavioral therapy (CBT) in elderly depressed outpatients.Clinical cohort study.University-affiliated hospital.Sixty outpatients (age 59 years and older) completed 12 weeks of CBT between July 2010 and December 2011. Forty-four completed fMRI procedures.The main outcome consisted of a conversion from a clinical diagnosis (Mini-International Neuropsychiatric Interview) of depression to no clinical diagnosis of depression or a significant improvement in diagnostic criteria. Brain activation measured by functional magnetic resonance imaging during the Wisconsin Card Sorting task (WCST) was the primary predictor variable.67% of patients had a positive response to CBT. Decreased activation in the left inferior frontal triangle and right superior frontal gyrus as well as increased activity in the right middle frontal gyrus and left superior frontal gyrus predicted a positive response to CBT. Demographic and neurocognitive measures of WCST performance were not significant predictors of a positive CBT outcome, whereas the measure of WCST-induced activity in the prefrontal cortex was a significant predictor.These data are among the first to suggest that measures of prefrontal brain activation during executive functioning predict response to CBT in older adults. Further exploration of the specific underlying processes that these prefrontal cortical regions are engaging that contributes to better CBT outcomes is warranted in larger, randomized studies.

Abstract

Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database.The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared.There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups.These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.

Abstract

The onset of bipolar disorder is influenced by the interaction of genetic and environmental factors. We previously found that a large increase in sunlight in springtime was associated with a lower age of onset. This study extends this analysis with more collection sites at diverse locations, and includes family history and polarity of first episode.Data from 4037 patients with bipolar I disorder were collected at 36 collection sites in 23 countries at latitudes spanning 3.2 north (N) to 63.4 N and 38.2 south (S) of the equator. The age of onset of the first episode, onset location, family history of mood disorders, and polarity of first episode were obtained retrospectively, from patient records and/or direct interview. Solar insolation data were obtained for the onset locations.There was a large, significant inverse relationship between maximum monthly increase in solar insolation and age of onset, controlling for the country median age and the birth cohort. The effect was reduced by half if there was no family history. The maximum monthly increase in solar insolation occurred in springtime. The effect was one-third smaller for initial episodes of mania than depression. The largest maximum monthly increase in solar insolation occurred in northern latitudes such as Oslo, Norway, and warm and dry areas such as Los Angeles, California.Recall bias for onset and family history data.A large springtime increase in sunlight may have an important influence on the onset of bipolar disorder, especially in those with a family history of mood disorders.

Abstract

Insulin resistance (IR) is a putative risk factor for cognitive decline and dementia, and has been shown to impede neuronal glucose metabolism in animal models. This post hoc study focused on metabolic changes in the medial prefrontal region, a brain region exhibiting decline years before documented cognitive changes, relative to high or low IR status in a cohort of postmenopausal women at risk for dementia who were randomized to continue or discontinue existing stable hormone therapy (HT) for 2 years. Subjects were dichotomized into high and low IR groups based on the homeostatic model assessment of insulin resistance, which was within clinically normal limits for the group as a whole at both baseline and 2-year follow-up. Results showed that high and low IR groups showed significant differences in metabolic decline of the medial prefrontal gyrus, regardless of HT randomization group. However, HT randomization was predictive of metabolic decline only in women with low HOMA (homeostatic assessment of insulin resistance). Performance in working memory was consistent with observed metabolic changes. These results suggest IR may be an independent moderator of regional metabolic changes, while protective metabolic effects of HT are most apparent in those at low-end range of IR. If replicated in future studies, these findings will help to better understand the interaction between putative risk and protective factors, and further delineate cohort postmenopausal women who may benefit from HT.

Abstract

Brain-derived neurotrophic factor (BDNF) protein has been implicated in the pathophysiology of mood disorders, with early data suggesting that blood levels may vary by severity of mood symptoms. BDNF polymorphism, val66met, has also been implicated in mood disorders.Euthymic women with bipolar disorder (BD) (n=47) and healthy control women (n=26), ages 18-45, were clinically rated using the Montgomery-Asberg Depression Rating Scale (MADRS) and sampled for plasma BDNF concentration, with a subset undergoing genetic analysis for the val66met.BD and control groups did not differ on any demographic variables, nor in plasma BDNF levels or val66met polymorphism. Plasma BDNF concentration did not differ by val66met or BD subtype, nor was it correlated with age or illness duration. Within women with BD, lower plasma BDNF concentrations were significantly associated with higher MADRS scores, even after controlling for psychotropic medication use and illness duration.The sample was relatively small and exclusive to women, with further research needed to investigate the links between BDNF markers and mood symptom severity in both men and women.The study provides a gender-specific investigation of plasma BDNF levels and mood, and the results add further evidence of a significant interplay between BDNF markers and psychiatric symptomatology. Further, this association did not appear to be confounded by use of psychotropic medication. Studies with larger samples of both genders are needed to further delineate this relationship.

Abstract

The purpose of the present study was to investigate the reproductive function of women with bipolar disorder (BD) compared to healthy controls.Women diagnosed with BD and healthy controls with no psychiatric history, aged 18-45 years, were recruited from a university clinic and surrounding community. Participants completed a baseline reproductive health questionnaire, serum hormone assessment, and ovulation tracking for three consecutive cycles using urine luteinizing hormone (LH)-detecting strips with a confirmatory luteal-phase serum progesterone.Women with BD (n = 103) did not differ from controls (n = 36) in demographics, rates of menstrual abnormalities (MAs), or number of ovulation-positive cycles. Of the women with BD, 17% reported a current MA and 39% reported a past MA. Dehydroepiandrosterone sulfate and 17-hydroxyprogesterone levels were higher in controls (p = 0.052 and 0.004, respectively), but there were no other differences in biochemical levels. Medication type, dose, or duration was not associated with MA or biochemical markers, although those currently taking an atypical antipsychotic agent indicated a greater rate of current or past MA (80% versus 55%, p = 0.013). In women with BD, 22% reported a period of amenorrhea associated with exercising or stress, versus 8% of controls (p = 0.064). Self-reported rates of bulimia and anorexia nervosa were 10% and 5%, respectively.Rates of MA and biochemical levels did not significantly differ between women with BD and controls. Current atypical antipsychotic agent use was associated with a higher rate of current or past MA and should be further investigated. The incidence of stress-induced amenorrhea should be further investigated in this population, as should the comorbid incidence of eating disorders.

Abstract

The objective of this study was to examine the effects of estrogen-based hormone therapy (HT) on regional cerebral metabolism in postmenopausal women (mean age?=?58, SD?=?5) at risk for development of dementia. The prospective clinical trial design included pre- and post-intervention neuroimaging of women randomized to continue (HT+) or discontinue (HT-) therapy following an average of 10 years of use. The primary outcome measure was change in brain metabolism during the subsequent two years, as assessed with fluorodeoxyglucose-18 positron emission tomography (FDG-PET). Longitudinal FDG-PET data were available for 45 study completers. Results showed that women randomized to continue HT experienced relative preservation of frontal and parietal cortical metabolism, compared with women randomized to discontinue HT. Women who discontinued 17-? estradiol (17?E)-based HT, as well as women who continued conjugated equine estrogen (CEE)-based HT, exhibited significant decline in metabolism of the precuneus/posterior cingulate cortical (PCC) area. Significant decline in PCC metabolism was additionally seen in women taking concurrent progestins (with either 17?E or CEE). Together, these findings suggest that among postmenopausal subjects at risk for developing dementia, regional cerebral cortical metabolism is relatively preserved for at least two years in women randomized to continue HT, compared with women randomized to discontinue HT. In addition, continuing unopposed 17?E therapy is associated specifically with preservation of metabolism in PCC, known to undergo the most significant decline in the earliest stages of Alzheimer's disease.ClinicalTrials.gov NCT00097058.

Abstract

Apolipoprotein-?4 (APOE-?4) is a major genetic risk factor for cognitive decline, Alzheimer's disease (AD) and early mortality. An accelerated rate of biological aging could contribute to this increased risk. Here, we determined whether APOE-?4 status impacts leukocyte telomere length (TL) and the rate of cellular senescence in healthy mid-life women and, further, whether hormone replacement therapy (HT) modifies this association. Post-menopausal women (N?=?63, Mean age?=?57.7), all HT users for at least one year, were enrolled in a randomized longitudinal study. Half of the participants (N?=?32) remained on their HT regimen and half (N?=?31) went off HT for approximately two years (Mean ?=?1.93 years). Participants included 24 APOE-?4 carriers and 39 non-carrier controls. Leukocyte TL was measured at baseline and the end of year 2 using quantitative polymerase chain reaction. Logistic regression analysis indicated that the odds of an APOE-?4 carrier exhibiting telomere shortening (versus maintenance/growth) over the 2-year study were more than 6 (OR ?=?6.26, 95% CI ?=?1.02, 38.49) times higher than a non-carrier, adjusting for established risk factors and potential confounds. Despite the high-functioning, healthy mid-life status of study participants, APOE-?4 carriers had marked telomere attrition during the 2-year study window, the equivalent of approximately one decade of additional aging compared to non-carriers. Further analyses revealed a modulatory effect of hormone therapy on the association between APOE status and telomere attrition. APOE-?4 carriers who went off their HT regimen exhibited TL shortening, as predicted for the at-risk population. APOE-?4 carriers who remained on HT, however, did not exhibit comparable signs of cell aging. The opposite pattern was found in non-carriers. The results suggest that hormone use might buffer against accelerated cell aging in mid-life women at risk for dementia. Importantly, for non-carrier women there was no evidence that HT conferred protective effects on telomere dynamics.

Abstract

Although bipolar disorder has high heritability, the onset occurs during several decades of life, suggesting that social and environmental factors may have considerable influence on disease onset. This study examined the association between the age of onset and sunlight at the location of onset.Data were obtained from 2414 patients with a diagnosis of bipolar I disorder, according to DSM-IV criteria. Data were collected at 24 sites in 13 countries spanning latitudes 6.3 to 63.4 degrees from the equator, including data from both hemispheres. The age of onset and location of onset were obtained retrospectively, from patient records and/or direct interviews. Solar insolation data, or the amount of electromagnetic energy striking the surface of the earth, were obtained from the NASA Surface Meteorology and Solar Energy (SSE) database for each location of onset.The larger the maximum monthly increase in solar insolation at the location of onset, the younger the age of onset (coefficient= -4.724, 95% CI: -8.124 to -1.323, p=0.006), controlling for each country's median age. The maximum monthly increase in solar insolation occurred in springtime. No relationships were found between the age of onset and latitude, yearly total solar insolation, and the maximum monthly decrease in solar insolation. The largest maximum monthly increases in solar insolation occurred in diverse environments, including Norway, arid areas in California, and Chile.The large maximum monthly increase in sunlight in springtime may have an important influence on the onset of bipolar disorder.

Abstract

Insulin resistance (IR) is the main pathological condition underlying vascular disorders, such as diabetes and cardiovascular disease, which are well established risk factors for cognitive decline and Alzheimer disease (AD). Hippocampal atrophy has been associated with cognitive decline, but little is known about the influence of IR on hippocampus integrity in non-diabetic, cognitively intact individuals. Herein, 50 women ages 50-65, current users of hormone therapy, underwent magnetic resonance imaging, cognitive testing, and homeostatic assessment of insulin resistance (HOMA-IR), as part of a longitudinal study examining brain structure and function in postmenopausal women at risk for AD. Results demonstrated a significant negative relationship between HOMA-IR and right and total hippocampal volume, overall cognitive performance, and selective tests of verbal and non-verbal memory. The main effect of HOMA-IR on brain structure and cognition was not altered by the presence of APOE-?4 allele or by reproductive history, such as duration of endogenous and exogenous estrogen exposure. These results suggest that IR in middle-aged individuals at risk for AD may be biomarker for dementia risk.

Abstract

Much controversy exists and many questions remain unanswered about the effects of hormone therapy (HT) on cognition in postmenopausal women. There is growing evidence suggesting that HT compounds containing conjugated equine estrogen (CEE) have negative effects on cognition whereas 17?-estradiol (17?-E) either has positive or neutral effects. The present study sought to further examine this issue in a sample of postmenopausal women with risk factors for Alzheimer's disease (AD).Cross-sectional neuropsychological evaluation.Academic research clinic.68 healthy postmenopausal women (aged 49-68) receiving either 17?-E or CEE for at least one year with increased risk for AD.Neuropsychological test battery of the cognitive domains of attention/working memory/processing speed, verbal memory, visual memory, and executive functioning.Multivariate analyses of variance (MANOVA) showed significantly better verbal memory performance in women receiving 17?-E compared to women receiving CEE regardless of age, IQ, years of education, risk factors for AD (including APOE-?4 carriership), duration of endogenous and exogenous estrogen exposure, concurrent progesterone use, or natural versus surgical menopause status.Verbal memory performance was better in postmenopausal women receiving 17?-E compared to CEE in a sample population of women with risk factors for AD. Genetic risk for AD as well as other confounds did not affect this finding. The results suggest a differential effect of HT type on verbal memory, with 17?-E being a preferential compound. Further evaluation of HT types, regimens and duration of use on cognitive performance in postmenopausal women in a controlled longitudinal design is warranted.

Abstract

Brief hypomania lasting less than 4 days may impair functioning and help to detect bipolarity. This study analyzed brief hypomania that occurred in patients with bipolar disorder who were diagnosed according to the DSM-IV criteria. Daily self-reported mood ratings were obtained from 393 patients (247 bipolar I and 146 bipolar II) for 6 months (75,284 days of data, mean 191.6 days). Episodes of hypomania were calculated using a 4, 3, 2, and single day length criterion. Brief hypomania occurred frequently. With a decrease in the minimum criterion from 4 days to 2 days, there were almost twice as many patients with an episode of hypomania (102 vs. 190), and more than twice as many episodes (305 vs. 863). Single days of hypomania were experienced by 271 (69%) of the sample. With a 2-day episode length, 33% of all hypomania remained outside of an episode. There was no significant difference in the percent of hypomanic days outside of an episode between patients with bipolar I and II disorders. There were no significant differences in the demographic characteristics of patients who met the 4-day minimum as compared with those who only experienced episodes of hypomania using a shortened length criterion. Decreasing the minimum length criterion for an episode of hypomania will cause a large increase in the number of patients who experience an episode and in the aggregate number of episodes, but will not distinguish subgroups within a sample who meet the DSM-IV criteria for bipolar disorder. Frequency may be an important dimensional aspect of brief hypomania. Clinicians should regularly probe for brief hypomania.

Abstract

Differential cerebral metabolic effects of various hormone therapy formulations, and their associations with cognitive status, remain to be established. The principal aim of the current study was to assess relationships between regional cerebral metabolism and estrogen-based hormone therapies. Postmenopausal women (n=53) at elevated risk for Alzheimer's disease (AD) were on estrogen-containing hormone therapy for at least one year prior to enrollment in a prospective, randomized clinical trial. Subjects underwent an FDG-PET scan, along with neuropsychological, medical, and demographic assessments at time of enrollment, to be repeated one year following randomization to hormone therapy continuation versus discontinuation, and results from analyses of the baseline assessments are reported here. Across all subjects, years of endogenous estrogen exposure correlated most closely with metabolism in right superior frontal gyrus (p<0.0005). Women taking 17?-estradiol (E) performed three standard deviations higher in verbal memory than women taking conjugated equine estrogen (CEE), and their verbal memory performance positively correlated with metabolism in Wernicke's (p=0.003) and auditory association (p=0.002) areas. Women taking progesterone-plus-estrogen had lower metabolism than women taking unopposed estrogen within the mesial and inferior lateral temporal regions (p<0.0005) and the inferior frontal cortex, contralateral to Broca's area (p<0.0005). In conclusion, particular areas of relatively preserved metabolism were seen in women with more years of endogenous estrogen exposure, as well as in women taking estradiol-based formulations or estrogen therapies unopposed by progesterone, together suggesting regionally specific neuroprotective estrogenic effects.

Abstract

BACKGROUND IVF, using donor oocytes, has become increasingly common. The donation procedure carries psychiatric risks, including depression, anxiety and rarely, psychosis, and this risk increases when there is a past history of psychiatric illness. We report on the psychiatric status, at intake assessment, of a group of candidate oocyte donors. METHODS The authors reviewed clinical records of 63 women continuously presenting to a University medical center for psychiatric evaluation as part of the screening process for oocyte donation. A board certified psychiatrist administered a structured clinical interview to candidate donors, and self-report measures were obtained from 28 women. RESULTS There was a significant discrepancy between psychiatric history of depression and current mood status, as measured by both clinical interview and psychometric self-report data. Nearly one-quarter of candidate donors (22%) reported a history of major depressive disorder; however, all candidate donors denied current mood disturbance on clinical interview, and mean Beck depression inventory and profile of mood states scores were lower than expected compared with psychometric norms (P < 0.0005), epidemiological data and the recurrent nature of depressive disorders. CONCLUSIONS Candidate donors may minimize psychiatric symptoms. Given the potential for ovarian stimulation protocols to induce or exacerbate mood symptoms, and the moderate heritability of mood disorders, careful evaluation of candidate donor affective disorder history is recommended. This evaluation should focus on sensitivity to mood destabilization during times of hormonal change. Measures that examine whether a candidate donor may have a tendency to present herself in an overly favorable manner, and/or a tendency to minimize symptoms, are recommended.

Abstract

Longer duration of reproductive years of life and thus greater exposure to endogenous estrogen may be associated with a lower risk of age-related diseases in women. The present study examined the relationship between estimated endogenous estrogen exposure and telomere length (TL) and telomerase activity, two biomarkers of cellular aging, in a sample of postmenopausal women at risk for cognitive decline. Telomere length was measured using a quantitative PCR method and telomerase activity by TRAP (Telomere-Repeats Amplification Protocol) assay in peripheral blood mononuclear cells (PBMCs). Study subjects were 53 postmenopausal women (35 with natural and 18 with surgical menopause) receiving hormone therapy (HT) for at least one year or longer. Length of reproductive years of life, computed as the difference between age at menopause and age at menarche, was used as a proxy of duration of exposure to endogenous estrogen. Length of time on HT was the measure used for duration of exogenous estrogen exposure. We found that longer endogenous estrogen exposure was associated with greater TL (standardized ?=0.06, Wald ?(2)=3.7, p=0.04) and with lower telomerase activity (standardized ?=-0.09, Wald ?(2)=5.0, p=0.03). Length of reproductive years was also inversely associated with the combination of short TL and high telomerase (OR=0.78, 95% CI: 0.63, 0.97, p=0.02). Length of HT use was not associated with TL or telomerase activity in this study. The results suggest that the endogenous estrogens may be associated with deceleration of cellular aging. This is the first study to examine associations between endogenous estrogens, telomere length and telomerase activity.

Abstract

There is broad consensus from epidemiologic research that lower socioeconomic status is related to poorer health. This study investigated the relation between median family income and self-reported mood symptoms in patients with bipolar disorder who reside in the United States.Two hundred eighty-four patients with bipolar disorder provided daily self-reported mood ratings for 6 months (50,054 days of data). Regardless of income, all patients were treated by a psychiatrist, took psychotropic medications, and participated in computerized self-monitoring throughout the study. Median family income was obtained from US census tract data. The association between income and mood was analyzed using income as both a continuous and categorical variable. Demographic characteristics were compared by income group. Education level was included in the analysis a priori.Both the continuous and categorical approaches found a positive association between income and euthymia, a negative association between income and manic/hypomanic symptoms including those due to mixed states, and no association between income and depressive symptoms. Patients in the lower-income group spent 12.4% fewer days euthymic than those in the upper-income group and 9.7% fewer days euthymic than those in the middle-income group. Patients in the lower-income group spent 7.1% more days with manic/hypomanic symptoms than those in the upper-income group. There was no association between education and income.Median family income is associated with mood symptoms in patients with bipolar disorder. Inclusion of income as a measure of socioeconomic status is recommended for future studies of outcome in bipolar disorder.

Abstract

This study compared subgroups identified by cluster analysis and clinical observation by evaluating the association between the age of onset of bipolar disorder and self-reported daily mood ratings.Two hundred and seventy patients with bipolar disorder provided daily self-reported mood ratings for about 6 months returning 55,188 days of data. The age of onset subgroups were determined both using previously defined cutoff values based upon clinical observation (?12 years, 13-19 years, 20-29 years, >29 years), and model-based cluster analysis. Demographic characteristics were compared in the age of onset subgroups. Univariate general linear models with age of onset subgroups and other demographic variables as fixed factors and covariates were used to analyze the percent of days depressed, euthymic and hypomanic/manic.Using the predetermined subgroups, demographic differences were found between the four subgroups in the diagnosis of bipolar I/II, years of illness, age and use of lamotrigine. Post-hoc pairwise comparison found that patients with an age of onset less ? 12 years spent more days hypomanic/manic: 16.4 percent versus 8.0 for patients with an age of onset between 13 and 19 years (p=0.006) and 8.2 percent for patients with an age of onset between 20 and 29 years (p = 0.031). The majority of the additional days of hypomania/mania occurred outside of an episode. Model-based cluster analysis found a mixture of 2 distributions of onset with peaks at age 15.1 years (SD = 4.7) and 27.5 years (SD = 10.2). Analysis of these two subgroups detected no significant differences in demographic characteristics or mood ratings.Age of onset subgroups arising from clinical observation may be more useful than those determined by cluster analysis.

Abstract

Overweight/obesity, insulin resistance (IR), and other types of metabolic dysfunction are common in patients with bipolar disorder (BD); however, the pathophysiological underpinnings of metabolic dysfunction in BD are not fully understood. Family history of type 2 diabetes mellitus (FamHxDM2), which has been shown to have deleterious effects on metabolic function in the general population, may play a role in the metabolic dysfunction observed in BD.Using multivariate analysis of variance, the effects of BD illness and/or FamHxDM2 were examined relative to metabolic biomarkers in 103 women with BD and 36 healthy, age-matched control women.As a group, women with BD had higher levels of fasting plasma insulin (FPI) and fasting plasma glucose (FPG), higher homeostatic assessment of IR (HOMA-IR) scores, body mass index (BMI), waist circumference (WC), and hip circumference (HC) compared to control women. FamHxDM2 was associated with significantly worse metabolic biomarkers among women with BD but not among healthy control women. Among women with BD, there was a significant main effect of FamHxDM2 on FPI, HOMA-IR, BMI, WC, and HC, even after controlling for type of BD illness, duration of medication exposure, and depression severity. Metabolic biomarkers were not influenced by use of weight-liable psychotropic medication (WLM), even after controlling for type of BD illness, duration of medication exposure, and depression severity.Women with BD have overall worse metabolic biomarkers than age-matched control women. The use of WLM, duration of medication use, type of BD illness, and depression severity did not appear to be associated with more pronounced metabolic dysfunction. FamHxDM2 may represent a risk factor for the development of IR in women with BD. Further, focused studies of the endocrine profiles of families of BD patients are needed.

Abstract

Neuroactive steroids (NAS) allopregnanolone (ALLO), Allotetrahydrodeoxycorticosterone (THDOC) and dehydroepiandrosterone (DHEA) are important in the regulation of mood and behavior. Knowledge about these steroids in postmenopausal depression and the effect of estrogen on NAS is lacking. We elected to determine if there were differences in NAS between postmenopausal depressed women and age matched controls. We also investigated the effect of estradiol on NAS in post menopausal depressed women receiving a selective serotonin reuptake inhibitor (SSRI), and in non-depressed postmenopausal controls. As part of a previously published double blind study on estrogen acceleration of antidepressant action, post menopausal women with major depression receiving sertraline and healthy non depressed controls were randomized to transdermal estrogen patch 0.1 mg or placebo. NAS were measured at baseline and after 10 weeks of treatment. Depressed subjects were treated with sertraline 50 mg/day to 100 mg/day for 9 weeks. At the baseline and after treatment ALLO and DHEA were significantly lower in depressed women compared to controls. Although all depressed subjects experienced a positive clinical response, estrogen administration was not associated with changes in NAS in either the depressed or the asymptomatic postmenopausal women. The lower ALLO and DHEA in postmenopausal depressed women suggests that symptoms of depression may be influenced by the synthesis or fluctuation of these NAS. Estradiol exposure did not alter ALLO, DHEA, or THDOC, implying these NAS are unlikely to play a role in any mood changes in post menopausal women given estrogen therapy.

Abstract

It is hypothesized that diabetes mellitus (DM) and mood disorders share points of pathophysiological commonality in the central nervous system.A PubMed search of all English-language articles published between 1966 and March 2009 was performed with the following search terms: depression, mood disorders, hippocampus, amygdala, central nervous system, brain, neuroimaging, volumetric, morphometric, and neurocognitive deficits, cross-referenced with DM. Articles selected for review were based on adequacy of sample size, the use of standardized experimental procedures, validated assessment measures, and overall manuscript quality. The primary author was principally responsible for adjudicating the merit of articles that were included.Volumetric studies indicate that individuals with Type 1/2 DM exhibit regional abnormalities in both cortical and subcortical (e.g., hippocampus, amygdala) brain structures. The pattern of neurocognitive deficits documented in individuals with Type 1 DM overlap with Type 2 populations, with suggestions of discrete abnormalities unique to each phenotype. The pattern of volumetric and neurocognitive deficits in diabetic populations are highly similar to that reported in populations of individuals with major depressive disorder.The prevailing models of disease pathophysiology in DM and major depressive disorder are distinct. Notwithstanding, the common abnormalities observed in disparate effector systems (e.g., insulin resistance, immunoinflammatory activation) as well as brain volume and neurocognitive performance provide the nexus for hypothesizing that both conditions are subserved by overlapping pathophysiology. This conception provides a novel framework for disease modeling and treatment development in mood disorder.

Abstract

We examined the relationships between regional brain activity and anxiety in bipolar depressed patients receiving adjunctive treatment with levothyroxine. Regional brain activity was assessed with positron emission tomography and [18F]fluorodeoxyglucose in 10 euthyroid, depressed bipolar women before and after 7 weeks of adjunctive therapy with levothyroxine. The primary biological measures were relative (to global) regional radioactivity as a surrogate index of glucose metabolism in pre-selected brain regions. Relationships were assessed between regional brain activity and anxiety symptoms while controlling for depression severity. At baseline, Trait Anxiety Inventory measures covaried positively with relative brain activity bilaterally in the dorsal anterior cingulate, superior temporal gyri, parahippocampal gyri, amygdala, hippocampus, ventral striatum, and right insula; state anxiety showed a similar pattern. After treatment anxiety was improved significantly. Change in trait anxiety covaried positively with changes in relative activity in right amygdala and hippocampus. Change in state anxiety covaried positively with changes in relative activity in the hippocampus bilaterally and left thalamus, and negatively with changes in left middle frontal gyrus and right dorsal anterior cingulate. Results indicate that comorbid anxiety symptoms have specific regional cerebral metabolic correlates in bipolar depression and cannot only be explained exclusively by the depressive state of the patients.

Abstract

A number of cross-sectional studies have suggested an association between insulin resistance (IR) and affective disorders. However, limited data exist on potential changes in IR in a prospective treatment of depression. The present pilot study tested the hypothesis that improvement of IR with the addition of an insulin-sensitizing agent would improve mood in nondiabetic patients with unipolar or bipolar depression, who had surrogate blood markers suggestive of IR. Surrogate IR-criteria blood markers were fasting plasma glucose >100 mg/dl or triglyceride (TG) to high density lipoprotein (HDL) ratio >3.0. Open-label rosiglitazone, titrated to a dose of 8 mg/day, was administered for 12 weeks to 12 patients with depressive disorder receiving treatment as usual (TAU). Eight patients who completed the 12-week study exhibited significant declines in both depression severity by the Hamilton Depression Rating Scale and the Clinical Global Impression scale, with moderate effect sizes noted. Modest improvement in Matsuda Index scores was also noted at 12 weeks, yet declines in depression severity scores were not associated with improvements in the endocrine markers (Matsuda Index, TG/HDL ratio, and body mass index). These results suggest the potential novel use for an insulin-sensitizing agent in the treatment of depressive disorders. Larger placebo-controlled studies are warranted.

Abstract

Polycystic Ovary Syndrome (PCOS) is a polygenic disorder caused by the interaction of susceptible genomic polymorphisms with environmental factors. PCOS, characterized by hyperandrogenism and menstrual abnormalities, has a higher prevalence in women with Bipolar Disorder (BD). Theories explaining this high prevalence have included the effect of PCOS itself or the effect of drugs such as Valproate, which may cause PCOS either directly or indirectly. Incidentally, metabolic abnormalities are observed in both bipolar and PCOS patients. Endophenotypes such as insulin resistance, obesity, and hyperglycemia are common among BD and PCOS patients, suggesting some degree of pathophysiological overlap. Since both BD and PCOS are complex polygenetic diseases, the endophenotype overlap may be the result of common genetic markers. This paper postulates that shared clinical endophenotypes between PCOS and BD indicate common pathophysiological platforms and will review these for the potential of genetic overlap between the two disorders.

Abstract

Psychosocial interventions may teach patients with bipolar disorder to successfully detect warning signs of relapse. These interventions often include ongoing self-monitoring of sleep. We previously reported that a change in sleep duration (sleep plus bedrest) of >3 h may indicate that a mood change is imminent. This analysis further investigated whether sleep duration, sleep onset or sleep offset was the most useful sleep/wake parameter to monitor for an oncoming mood change.101 adult outpatients receiving treatment as usual recorded mood, sleep and medications every day on a home computer for a mean of 265+/-103 days. A daily time series of mood, sleep duration (sleep plus bedrest), sleep onset and sleep offset was constructed for each patient. After applying an ARIMA (0,1,1) filter, a cross correlation function was used to analyze the temporal relationship between the residuals for lags of +/-7 days.Less frequent significant correlations were found between a change in either sleep onset or sleep offset and mood, than between sleep duration and mood. Patients with a significant correlation between sleep duration and mood included 86% of those with a significant correlation between sleep onset or sleep offset and mood. Mean sleep duration when euthymic was long (> or =8 h in 89% of patients, > or =9 h in 51% of patients).Self-reported data, naturalistic study, and computer access required.Self-monitoring of sleep duration is recommended for patients with bipolar disorder. Better understanding of the long sleep duration of euthymic patients is required.

Abstract

This study investigated the frequency of episodes and subsyndromal symptoms based on employment status in patients with bipolar disorder.Patients with bipolar disorder (n = 281) provided daily self-reported mood ratings for 5 months, returning 46,292 days of data. Data were analyzed using three employment status groups: disabled (n = 75), full-time employee or full-time student (n = 135), and other (n = 71). Demographic characteristics were compared by employment status. A univariate general linear model with employment status and other demographic variables as fixed factors and covariates was used to analyze the percent of days in episodes and percent of days with subsyndromal symptoms.While there was no significant difference in the percent of days in episodes among the employment groups, disabled patients suffered subsyndromal symptoms of depression twice as frequently as those in the full-time group. Disabled patients spent 15% more days either in episodes or with subsyndromal symptoms than those in the full-time group, equivalent to about 45 extra sick days a year.Frequent subsyndromal symptoms, especially depressive, may preclude full-time responsibilities outside the home and contribute to disability in bipolar disorder. Additional treatments to reduce the frequency of subsyndromal symptoms are needed.

Abstract

Many researchers have analyzed seasonal variation in hospital admissions for bipolar disorder with inconsistent results. We investigated if a seasonal pattern was present in daily self-reported daily mood ratings from patients living in five climate zones in the northern and southern hemispheres. We also investigated the influence of latitude and seasonal climate variables on mood.360 patients who were receiving treatment as usual recorded mood daily (59,422 total days of data). Both the percentage of days depressed and hypomanic/manic, and the episodes of depression and mania were determined. The observations were provided by patients from different geographic locations in North and South America, Europe and Australia. These data were analyzed for seasonality by climate zone using both a sinusoidal regression and the Gini index. Additionally, the influence of latitude and climate variables on mood was estimated using generalized linear models for each season and month.No seasonality was found in any climate zone by either method. In spite of vastly different weather, neither latitude nor climate variables were associated with mood by season or month.Daily self-reported mood ratings of most patients with bipolar disorder did not show a seasonal pattern. Neither climate nor latitude has a primary influence on the daily mood changes of most patients receiving medication for bipolar disorder.

Abstract

Emerging data suggest the menopausal transition may be a time of increased risk for depression. This study examines the course of bipolar disorder focusing on depressive symptoms in menopausal transition age women, compared to similar-aged men as well as younger adult women and men.Outpatients with bipolar disorder were assessed with the systematic treatment enhancement program for bipolar disorder (STEP-BD) affective disorders evaluation and longitudinally monitored during naturalistic treatment with the STEP-BD clinical monitoring form. Clinical status (syndromal/subsyndromal depressive symptoms, syndromal/subsyndromal elevation or mixed symptoms, and euthymia) was compared between menopausal transition age women (n=47) and pooled similar-aged men (n=30) 45-55 years old, younger women (n=48) and men (n=39) 30-40 years old.Subjects included 164 bipolar disorder patients (67 type I, 82 type II, and 15 not otherwise specified), 34% were rapid cycling and 58% women. Bipolar II disorder/bipolar NOS was more common in women. Monitoring averaged 30+/-22 months, with an average of 0.9+/-0.5 clinic visits/month. Menopausal age women had a significantly greater proportion of visits with depressive symptoms (p<0.05), significantly fewer euthymic visits (p<0.05) and no difference in proportion of visits with elevated/mixed symptoms compared to pooled comparison group.Menopausal transition age women with bipolar disorder experience a greater proportion of clinic visits with depressive symptoms compared to similarly aged men, and younger women and men with bipolar disorder. Further systematic assessment on the influence of the menopausal transition and reproductive hormones upon mood is needed to better inform clinical practice in treating women with bipolar disorder.

Abstract

To determine the effects of memantine on cognition in a normal population of postmenopausal women with putative risk factors for Alzheimer's disease (AD) using a built-in control for the genetic risk factor for AD (apoE-epsilon4 status).A prospective, open-label, 6-month pilot medication trial with memantine and follow-up after discontinuance conducted at the Center for Neuroscience in Women's Health, Stanford University School of Medicine. Neuropsychological data were collected on 22 community-dwelling postmenopausal women (11 apoE-epsilon4 carriers and 11 apoE-epsilon4 non-carriers) with at least one putative risk factor for AD.ApoE-epsilon4 status was not a significant predictor of change in neuropsychological performance. Changes associated with memantine treatment for entire sample included significant declines in some variables associated with verbal learning and memory that improved upon medication withdrawal. A positive medication effect was noted with executive functions and possibly category fluency. Trend-level improvements were seen in motor dexterity of the non-dominant hand and maintained even after drug discontinuance.Treatment with memantine appeared to have differential effects on cognitive performance in a population of women with putative risk factors for AD. ApoE-epsilon4 carrier status did not account for observed changes in cognition.

Abstract

The metabolic syndrome and its components are associated with depressive symptomatology. This article discusses the rate of co-occurrence and the points of pathophysiologic commonality between the metabolic syndrome and major depressive disorder.

Abstract

Cumulative data on the effects of estrogen therapy (ET) on brain function in postmenopausal women suggests that ET influences cerebral metabolism and may protect against age-related declines in various domains of cognitive function. The beneficial cognitive effects of ET may relate to its modulation of the thalamic-striatum cholinergic and dopaminergic systems, as the activity of both neurotransmitter systems in the thalamus appears to be positively influenced by estrogen. In the current study, we attempted to evaluated regional cerebral brain metabolism utilizing [18F]-fluorodeoxyglucose positron emission tomography in 11 healthy recently-postmenopausal women on ET (ET+) in comparison to 11 recently-postmenopausal and ET-naïve women (ET-) in order to assess the effects of ET on cholinergic and dopaminergic system regulation. Results showed thalamo-basal ganglia connectivity among ET+ women but not among ET- women. The presence of connectivity in the thalamo-striatal pathway in recently postmenopausal women suggests estrogen effects in preserving integrity of the cholinergic and dopaminergic systems. The results also suggest that ET initiated at or near the menopausal transition may modulate brain aging by mediating complex sensory-motor functions.

Abstract

Women with mood disorders, especially bipolar disorder (BD), have been shown to have high rates of reproductive and metabolic dysfunction. The available data on the functional, anatomic, and clinical neuroendocrine abnormalities in women with BD suggest a two-tiered relationship with mood pathology. First, many of the medications commonly used in the treatment of BD can have deleterious effects on blood levels of reproductive hormones and consequently on the hypothalamic-pituitary-gonadal (HPG) axis and reproductive function. Studies that have specifically addressed the association between psychotropic medications and menstrual abnormalities, polycystic ovary syndrome, and overall reproductive endocrine function in women with BD have found high rates of HPG irregularities in women with BD. Second, there is evidence of reproductive dysfunction in women with BD prior to treatment. In addition, many of the psychotropic medications used in the treatment of BD are associated with weight gain, insulin resistance, and dyslipidemia. These metabolic side effects further compound the neuroendocrine system dysregulation in women with BD. Current understanding of the reproductive and metabolic function in women with BD points to vulnerability, which in turn increases the risk of later-life cardiovascular disease and diabetes, among other morbidities, for women with BD.

Abstract

Cerebral metabolic rates were assessed using [(18)F]-fluorodeoxyglucose positron emission tomography in six naturally postmenopausal women with untreated unipolar depression and 11 matched controls. All subjects were hormone therapy-naive and medication-free. Findings include hypermetabolism in the middle frontal gyrus and Broca regions, and hypometabolism in the pons among depressed compared with non-depressed women.

Abstract

With the widespread recognition of the value of active patient participation in their care, ChronoRecord software was developed to automate daily self-reporting by patients with bipolar disorder. A prior study demonstrated concurrent validity between self-ratings on ChronoRecord and clinician ratings on the Hamilton Depression Rating Scale (HAMD), but validity with the Young Mania Rating Scale (YMRS) could not be shown due to a lack of data when the outpatients were manic (Bauer et al., Bipolar Disorders 6, 67-74, 2004). This study expanded upon the prior validation study to include inpatients with mania. Self-reported mood ratings on ChronoRecord and clinician ratings on the YMRS were obtained on the same day from 27 inpatients (57 ratings); these data were also combined with the ratings from the 80 outpatients (total 107 patients, 340 ratings). Using Pearson correlation, the self-reported ratings on ChronoRecord were significantly correlated with the YMRS. The accuracy of ChronoRecord to discriminate hypomania and mania was high, as described by the area under the receiver operating characteristic curve. Post-hoc analysis of the level of agreement between ChronoRecord and YMRS ratings was excellent or good in all cases using the kappa statistic. These data demonstrate concurrent validity between ChronoRecord and YMRS.

Abstract

Data are emerging in bipolar disorder regarding mood across phases of the female reproductive life, yet information about mood during the menopausal transition remains limited. The menopausal transition in women without mood disorders is associated with an increase in depression. This study assesses mood course during the menopausal transition in women with bipolar disorder.We monitored mood episodes in 47 women with bipolar disorder ages 45-55 for 17.0+/-14.0 months with systematic treatment enhancement program for bipolar disorder (STEP-BD) standardized evaluations. Charts were additionally reviewed for menstrual status and menstrual history, as well as mood episode type, duration, frequency and history.During the menopausal transition 68% of women with bipolar disorder experienced at least one depressive episode. Depression (but not mood elevation) episode frequency significantly increased during the menopausal transition compared to reported frequency during patients' reproductive years. History of pre-menstrual and or post-partum mood instability did not predict perimenopausal mood episodes.Women with bipolar disorder experience a high frequency of depressive episodes during perimenopausal years and this frequency appears greater than during prior reproductive years. Prospective controlled studies are needed to better understand the course of mood episodes and to enhance the effectiveness of managing bipolar disorder during the menopausal transition.

Abstract

Children of persons with Alzheimer disease (AD), as a group, face an increased risk of developing AD. Many of them, throughout their adult lives, seek input on how to reduce their chances of one day suffering their parent's fate. We examine the state of knowledge with respect to risk and protective factors for AD and recommend a research agenda with special emphasis on AD offspring.

Abstract

A medline literature review of fertility and mood disorder articles published since 1980 was performed in order to critically review the literature regarding a relationship between mood disorders, fertility and infertility treatment. Previous studies suggests that mood disorders, both in the bipolar and unipolar spectrum, may be associated with decreased fertility rates. Most studies report that women seeking treatment for infertility have an increased rate of depressive symptoms and possibly major depression (none showed evaluated mood elevations). Many, but not all, studies found that depressive symptoms may decrease the success rate of fertility treatment. Treatments for infertility may independently influence mood through their effects on estrogen and progesterone, which have been shown to influence mood through their actions on serotonin. Studies are limited in scope and confounding variables are many, limiting the strength of the results. In conclusion, a range of existing studies suggests that fertility and mood disorders are related in a complex way. Future studies should use clinical interviews and standardized and validated measures to confirm the diagnosis of mood disorders and control for the variables of medication treatment, desire for children, frequency of sexual intercourse, age, FSH levels, menstrual cycle regularity in assessing an interrelationship between mood disorders and fertility.

Abstract

Patients with bipolar disorder often report depressive symptoms that do not meet the DSM-IV criteria for an episode. Using daily self-reported mood ratings, we studied how changing the length requirement to that typical of recurrent brief depression (2-4 days) would impact the number of depressed episodes.203 patients (135 bipolar I and 68 bipolar II by DSM-IV criteria) recorded mood daily using ChronoRecord software on a home computer (30,348 total days; mean 150 days). Episodes of depression and days of depression outside of episodes were determined. Symptom intensity (mild versus moderate or severe) was investigated within and outside of depressive episodes.Decreasing the minimum duration criterion for an episode of depression to 2 days increased the number of patients with a depressed episode two and a half times (52 to 131), and quadrupled both the number of depressed episodes per patient (0.62 to 2.88) and the number of depressed episodes for all patients (125 to 584). With a 2-day episode length, 34% of days of depression remained outside an episode. The ratio of days with severe symptoms within episodes remained consistent (about 25%) in spite of decreasing the episode length to 2 days. Considering only days with severe symptoms, about 25% remained outside of episodes even with a 2-day length. None of the results distinguished bipolar I from bipolar II disorder.Self-reported data, computer access required, relatively short study length, no control group.Brief depressive episodes and single days of depression outside of episodes occur frequently in both bipolar I and bipolar II disorder. Moderate or severe symptoms occur during brief episodes at a ratio similar to that for episodes that meet the DSM-IV criteria.

Abstract

The effects of inadequate thyroid hormone availability to the brain on adult cognitive function are poorly understood. This study assessed the effects of hypothyroidism on cognitive function using a standard neuropsychological battery in 14 patients suffering from untreated hypothyroidism and complaining of subjective cognitive difficulties in comparison with 10 age-matched healthy comparison subjects. Significant differences between groups were limited to verbal memory retrieval as measured by the California Verbal Learning Test (CVLT). On short delay free recall, long delay free recall, and long delay cued recall, significant differences remained between groups despite the limited statistical power of this study. There were no significant results found between groups on attentional or nonverbal tasks. Results suggest that hypothyroid-related memory deficits are not attributable to an attentional deficit but rather to specific retrieval deficits.

Abstract

Pilot study examining the effects of estrogen therapy (ET) on antidepressant response in postmenopausal women with major depressive disorder (MDD).Twenty-two subjects received sertraline at 50mg/day for one week, with an increase to 100mg/day at week 2 for a 10-week trial. Transdermal estrogen or placebo patches 0.1mg were randomly administered concurrent with the initiation of sertraline treatment. The 21 item Hamilton Depression Rating Scale (HDRS-21) was administered to all patients at baseline and weekly thereafter.Both groups showed a similar significant reduction in HDRS-21 scores by the end of the study. There was no significant difference between the two treatment groups at the end of the 10-week trial, but the women receiving sertraline with ET showed significantly greater early improvement (weeks 2-4) compared to the women receiving sertraline with placebo.Sertraline is an effective antidepressant for postmenopausal women with MDD. ET does not alter the response rate to antidepressant therapy however ET may play a role in accelerating the antidepressant response.

Abstract

Disturbance of each of the three hypothalamic-pituitary-end organ systems [hypothalamic-pituitary-thyroid (HPT), -adrenal (HPA), and -gonadal (HPG)] has been reported in depressive disorders. Little is known about potential reciprocal interaction among the three HP-end organ systems in patients with depressive disorders. The present pilot study examined selective HPA and HPG hormones in a detailed time series in women with bipolar disorder (depressed type) before and after treatment with levothyroxine (L-T4), and in matched control subjects. Six medically stable, euthyroid, premenopausal women with bipolar depression, and 5 age-matched controls underwent overnight blood sampling from 2100 to 0900 h for measurement of adrenocorticotropic hormone (ACTH), cortisol, luteinizing hormone (LH), and estradiol every 15 min. Bipolar patients underwent a second overnight blood sampling procedure following 7-weeks of open-label add-on treatment with L-T4. Results revealed lower baseline cortisol parameters in bipolar patients in comparison to control subjects, while ACTH, LH, and estradiol parameters were similar. Thyroid hormones (TSH, free and total T4) were not correlated with any of the HPA or HPG hormones. ACTH and cortisol levels were correlated in control subjects, but not in bipolar patients. After L-T4 treatment, thyroid hormones increased significantly and depression scores significantly declined. No significant changes in HPA or HPG hormones parameters were observed, although the small sample size may have limited results. Upon visual inspection, ACTH and cortisol appeared to decrease after L-T4 treatment, while estradiol appeared to increase. These pilot data suggest lower levels of cortisol in women with bipolar depression, unlike previously published studies that reported higher cortisol in patients with depression. The data also suggest reciprocal changes in the HPA and HPG axes upon pharmacological modulation of the HPT system, although whether this change was due to the L-T4 treatment or the improvement of depression is unknown. The results are preliminary, and require replication in larger samples.

Abstract

Valproic acid (2-n-propylpentanoic acid, VPA) is well-established as a mood-stabilizer for bipolar disorder, in addition to its application as a treatment in neurological disorders such as epilepsy, migraine headaches, and chronic neuropathic pain. Its mechanisms of actions in any of the disorders have not yet been fully elucidated but currently include GABA-ergic inhibitory effects, the suppression of NMDA-mediated excitatory neurotransmission, and possibly effects on monoamines and cerebral glucose metabolism. Given the rising use of VPA by women of reproductive age for various conditions it is increasingly important to understand how VPA affects reproductive and metabolic function in women, yet a number of key issues regarding VPA use in women of reproductive age remain unclear. These include the question of whether VPA use is associated with the development of polycystic ovary syndrome (PCOS)-like features (such as elevated androgen concentrations and/or chronic anovulation). The metabolic effects of VPA use, particularly on insulin sensitivity and weight gain, are also important to understand. Lastly, questions of VPA use during pregnancy and lactation require continued attention. This article reviews the current understanding of VPA's mechanisms of action, effects on the reproductive and metabolic system, and teratogenic qualities, highlighting important future areas of study.

Abstract

Some investigators have suggested decreasing the minimum hypomania episode length criterion from 4 days, as in the DSM-IV, to 2 days. Using daily self-reported mood ratings, we studied the impact of changing the length requirement on the number of hypomanic episodes in patients with bipolar disorder.203 patients (135 bipolar I and 68 bipolar II by DSM-IV criteria) recorded mood daily using ChronoRecord software (30,348 total days, mean 150 days). Episodes of hypomania and days of hypomania outside of episodes were determined.Decreasing the minimum duration criterion for an episode of hypomania from 4 to 2 days doubled the mean percent of days in a hypomanic episode for each patient (4% to 8%), doubled the number of patients with a hypomanic episode (44 to 96) and increased the number of hypomanic episodes for all patients about three-fold (129 to 404). With a minimum episode length of 4 days, bipolar I patients were more likely to report hypomania outside episodes than bipolar II patients (p=0.010), but with a length of 2 or 3 days there was no significant difference in the distribution of hypomania outside of episodes by diagnosis. With a 2-day length, about one-third (36%) of hypomania remained outside of an episode.Self-reported data, computer access, relatively short length, fewer bipolar II than bipolar I patients.As the minimum length for an episode of hypomania decreases, there was a large increase in both the number of episodes and number of patients with episodes. One-day hypomania outside of episodes occurs frequently in both bipolar I and bipolar II disorder.

Abstract

Approximate entropy (ApEn) measures regularity in time series data, while traditional linear statistics measure variability. Using self-reported mood data from patients with bipolar disorder, this preliminary study addressed whether ApEn could distinguish (i) the 60 days prior to the start of a manic or depressed episode from the 60 days prior to a month of euthymia, and (ii) the 60 days prior to a manic episode from the 60 days prior to a depressed episode.Self-reported mood data from 49 outpatients with bipolar disorder receiving standard treatment were analysed. The data contained 27 episodes (12 manic and 15 depressed), and 43 periods of 1 month of euthymia. For the 60 days prior to episode or euthymia, the ApEn, linear statistics and the correlation between linear and non-linear measures were calculated.ApEn was significantly greater in the 60 days prior to a manic or depressive episode than the 60 days prior to a month of euthymia. The onset of an episode was associated with greater irregularity in mood. Variability was also significantly larger and correlated with ApEn. ApEn was significantly greater in the 60 days prior to a manic episode than in the 60 days prior to a depressed episode, whereas measures of variability were not significantly different. Mood in the 60 days prior to mania was more irregular than prior to depression.Non-linear measures may complement traditional linear measures in the analysis of longitudinal data in bipolar disorder. A larger study is indicated.

Abstract

This study assessed mood and neuropsychological function in a population of middle-aged women with major depressive disorder treated with escitalopram.Psychometric data measuring severity of depression were collected from 19 women and neuropsychological data were collected from 17 women aged between 45 and 65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of major depression in a study in the Behavioral Neuroendocrinology Program at the Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine. All women were treated with escitalopram in an open-label design. Mean age was 55.94 years and mean number of years of education was 16.36 years. Diagnosis of major depressive disorder was assessed with the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and mood was evaluated with the 21-item Hamilton Depression Rating Scale (HAM-D) at baseline and at weekly follow-ups for 12 weeks. Cognition was assessed at baseline and 3 months after treatment using a neuropsychological test battery, which included an abbreviated measure of Full Scale Intelligence Quotient, measures of attention and processing speed, verbal and nonverbal memory, executive functioning, and verbal fluency. Self-report data were collected on current menopause status and current hormone therapy use in the postmenopausal women. Paired sample t tests were used to analyze the change in total HAM-D scores and neuropsychological variables.Statistically significant improvements were found in total HAM-D score, Wechsler Memory Scale III Logical Memory 1st Recall, I, and II scores, Wechsler Memory Scale III Visual Reproduction I scores, and Trail Making Test Part B scores. There was a statistically significant decrease in Controlled Oral Word Association Test FAS scores.Treatment of depression with escitalopram in a population of middle-aged women was shown to improve mood and cognitive efficiency in complex attention, short- and long-term recall of contextual information, short-term recall of visual information, and cognitive flexibility; however, it was shown to worsen phonemic fluency.

Abstract

The consequences of inadequate thyroid hormone availability to the brain and treatment effects of levothyroxine on cognitive function are still poorly understood. This study prospectively assessed the effects of thyroid replacement therapy on cognitive function in patients suffering from biochemical evidenced, untreated hypothyroidism. Significant effects between the untreated hypothyroid group and control group were limited to verbal memory retrieval. When assessing the effects of 3-month treatment, results revealed that the treated hypothyroid group had significant increased verbal memory retrieval. Results suggest that specific memory retrieval deficits associated with hypothyroidism can resolve after replacement therapy with levothyroxine.

Abstract

This prospective, longitudinal study compared the frequency and pattern of mood changes between outpatients receiving usual care for bipolar disorder who were either taking or not taking antidepressants. One hundred and eighty-two patients with bipolar disorder self-reported mood and psychiatric medications for 4 months using a computerized system (ChronoRecord) and returned 22,626 days of data. One hundred and four patients took antidepressants, 78 did not. Of the antidepressants taken, 95% were selective serotonin or norepinephrine reuptake inhibitors, or second-generation antidepressants. Of the patients taking an antidepressant, 91.3% were concurrently taking a mood stabilizer. The use of antidepressants did not influence the daily rate of switching from depression to mania or the rate of rapid cycling, independent of diagnosis of bipolar I or II. The primary difference in mood pattern was the time spent normal or depressed. Patients taking antidepressants frequently remained in a subsyndromal depression. In this naturalistic study using self-reported data, patients with bipolar disorder who were taking antidepressants--overwhelmingly not tricyclics and with a concurrent mood stabilizer--did not experience an increase in the rate of switches to mania or rapid cycling compared to those not taking antidepressants. Antidepressants had little impact on the mood patterns of bipolar patients taking mood stabilizers.

Abstract

Early recognition of the prodromal symptoms of bipolar disorder, combined with a patient action plan, may help to prevent relapses. Sleep disturbances are frequent warning signs of both mania and depression. This study used cross correlation analysis to characterize the relationship between mood, sleep and bedrest in longitudinal data.Self-reported mood, sleep and bedrest (mean 169 +/- 59 days of data per patient) from 59 outpatients with bipolar disorder receiving standard treatment were analyzed. The cross correlation function was used to determine the latency between the changes in sleep and/or bedrest and mood for time shifts of between -7 and 7 days.For sleep and/or bedrest, a significant inverse correlation was found with the change in mood, most commonly with a time latency of one day. Sleep plus bedrest had the strongest relationship with a change in mood, with a significant correlation in 24 of 59 patients (41%) for the night before or night of a mood change. The patients with a significant cross-correlation between mood and sleep plus bedrest reported about two thirds of all large sleep changes of >3 h and three fourths of all large mood changes (>20 on 100-unit scale). Patients with a significant cross correlation were more likely to take benzodiazepines.In most patients with a significant cross correlation between sleep and/or bedrest and mood, the mood change occurred on the day following the change in sleep and/or bedrest. Sleep changes from a previous pattern, especially those of more than 3 h, may indicate that a large mood change is imminent.

Abstract

Hepatic encephalopathy (HE) is normally diagnosed by neuropsychological (NP) tests, which are not very specific and do not reveal the underlying pathology. Magnetic resonance imaging (MRI) and spectroscopy (MRS) of the brain offer alternative and possibly more specific markers for HE. These methods were applied in conjunction with NP testing in order to determine their usefulness in the identification of HE and to understand the pathogenesis of HE more clearly. MR imaging and spectroscopy examinations, in addition to a battery of 15 NP tests, were administered to investigate 31 patients awaiting liver transplantation and 23 healthy controls. MR image intensities from the globus pallidus region were calculated and normalized to those of the thalamus. Absolute concentrations and ratios with respect to creatine (Cr) of several metabolites were computed from MR spectra. The MR data were correlated with the results of NP tests. The patients showed impairment in NP tests of attention and visuospatial and verbal fluency. In T1-weighted MRI, the relative intensity of the globus pallidus with respect to that of the thalamus region was significantly elevated in patients and correlated(negatively) with three NP tests (Hooper, FAS, and Trails B). The absolute concentrations of myo-inositol (mI) and choline (Ch) were significantly reduced in three brain regions. In addition, the absolute concentrations of glutamine (Gln) and combined glutamate and glutamine (Glx) were increased in all three locations, with Gln increase being significant in all areas while that of Glx only in the occipital white matter. In summary, this study partially confirms a hypothesized mechanism of HE pathogenesis, an increased synthesis of glutamine by brain glutamate in astrocytes due to excessive blood ammonia, followed by a compensatory loss of myo-inositol to maintain astrocyte volume homeostasis. It also indicates that the hyperintensity observed in globus pallidus could be used as complementary to the NP test scores in evaluating the mental health of HE patients.

Abstract

Several lines of evidence suggest an association between depressive disorders and Alzheimer's disease (AD). We previously suggested central nervous system (CNS) effects of insulin resistance (IR) to be an important link between depressive disorders and AD. Although the exact mechanism of central IR is not known, it is thought that central IR results in inadequate glucose metabolism in the brain. According to our hypothesis, inadequate glucose utilization resulting from IR underlies neuronal changes in crucial brain regions (i.e. limbic system) observed among patients with depressive disorders, the same brain regions affected in AD. Further, in patients with undetected and/or untreated IR, such changes in glucose utilization, if unresolved, may lead to neurodegeneration. Our studies have demonstrated a high prevalence of IR in patients with depressive disorders, and reciprocally, a high prevalence of depression in patients with the primary IR disorder polycystic ovary syndrome (PCOS), and we believe these populations have significantly increased risk of cognitive decline. Herein, we review the IR link in depressive disorders and AD and describe the results of our studies and others in support of this hypothesis.

Abstract

We assessed reproductive endocrine and metabolic markers in women treated for bipolar disorder over a 2-year time period, controlling for valproate use.Twenty-five women ages 18-45 with bipolar disorder underwent longitudinal evaluations. Subjects completed a reproductive health questionnaire and endocrinological exam at baseline. Total and free testosterone, progesterone, LH, FSH, fasting insulin and glucose, and other hormones were measured across the menstrual cycle at baseline and at 2-year follow-up.Ten subjects were currently receiving valproate as a mood stabilizing agent; of the remaining subjects, six received lithium and five received atypical antipsychotics. Of all subjects, 41.7% reported current oligomenorrhea, while 40% reported oligomenorrhea before starting medication. Rates of oligomenorrhea and clinical hyperandrogenism did not differ by medication use. Eighty percent of women had a high homeostatic model assessment of insulin resistance (HOMA-IR) at baseline; all other measures were normal. Over time, all subjects exhibited a significant decrease in luteal phase progesterone and increase in free testosterone concentrations. Valproate use was associated with an increase over time in total testosterone. Baseline values and changes in BMI were similar across groups.Limitations include small sample size and the absence of a control group.We confirm our previous observations of high rates of menstrual abnormalities, hyperandrogenemia and insulin resistance in women with bipolar disorder. These results tentatively support the role of valproate in hyperandrogenemia; however, rates of oligomenorrhea and clinical hyperandrogenism did not differ between medication groups.

Abstract

The objective of this pilot study on a convenience sample of 25 offspring of Alzheimer patients (mean age 61.5 +/- 8.8 years; range, 50-82) was the early detection of neurocognitive decline. This preliminary report appears to be the first one dealing with 20-year follow-up of neurocognitive data of Alzheimer's disease (AD) children. Digit symbol (Wechsler Adult Intelligence Scale) was the only of 11 neurocognitive measures with a significant decline. And that decline between first and last testing (mean = 19.98 +/- 0.30 years) was on raw scores, not scaled scores. Neither parents' age at onset of AD nor autopsy confirmation or offspring APOE-e4 status influenced neurocognitive results. More robust data than currently available are needed to confirm the findings of this first pilot study and to determine both the trajectory of neurocognitive decline in AD and the risks of developing AD faced by children whose parent had the disease.

Abstract

Patients with psychiatric disorders have an increased rate of cardiovascular morbidity and mortality compared with the general population. Metabolic issues such as weight gain, dyslipidemia, diabetes mellitus, diabetic ketoacidosis,and pancreatitis have been reported with the use of antipsychotic agents. Although atypical antipsychotics have not been linked directly to the development of metabolic syndrome, these medications have been shown to increase risk factors that can lead to metabolic and endocrine disturbances. Therefore, clinicians should provide ongoing monitoring for patients who are being treated for psychiatric disorders with these agents. According to the 2004 Consensus Report on Antipsychotics, screening measures should include baseline and follow-up monitoring of personal/family histories, weight (body mass index), waist circumference, blood pressure, fasting plasma glucose, and fasting lipid profile.

Abstract

To analyze the risk of cognitive impairment among female Swedish Twins with regard to endogenous and exogenous hormone exposure.A cross-sectional analysis of data from the HARMONY Study, a population-based cohort study of cognitive impairment in the Swedish Twin Registry.Information regarding age at menarche and menopause, parity, and length and type of hormone therapy (HT) was collected via a telephone interview from 6604 women, aged 65-84. Cognitive impairment was assessed with the TELE, a brief telephone cognitive screen.Length of reproductive period was inversely associated with risk of cognitive impairment (p<0.01). The OR was 1.15 (CI 95% 0.96-1.36) for women with reproductive periods <35 years and 0.82 (CI 95% 0.66-1.00) for women with reproductive periods >39 years. Age at menopause was inversely associated with risk of cognitive impairment. Use of HT was associated with average 40% decline in the risk of cognitive impairment, independent of type and timing of treatment.Our results suggest that both increased length of reproductive period and HT are associated with reduced risk of cognitive impairment.

Abstract

This study examined the reproductive function and prevalence of polycystic ovary syndrome (PCOS) in women with bipolar disorder taking antimanic medications.Women aged 18-45 treated for bipolar disorder and not taking steroid contraceptives were recruited to complete questionnaires about their menstrual cycle and to provide blood samples for measurement of a range of reproductive endocrine and metabolic hormone levels. Eighty women participated in completing the questionnaires and 72 of them provided blood samples.Fifty-two of the 80 women (65%) reported current menstrual abnormalities, 40 of which (50%) reported one or more menstrual abnormalities that preceded the diagnosis of bipolar disorder. Fifteen women (38%) reported developing menstrual abnormalities since treatment for bipolar disorder, 14 of which developed abnormalities since treatment with valproate (p = 0.04). Of the 15 patients reporting menstrual abnormalities since starting medication, 12 (80%) reported changes in menstrual flow (heavy or prolonged bleeding) and five (33%) reported changes in cycle frequency. No significant differences were observed between women receiving or not receiving valproate in mean levels of free or total serum testosterone levels. This was true for the total sample and for the sub-group without preexisting menstrual problems. However, within the valproate group, duration of use was significantly correlated with free testosterone levels (r = 0.33, p = 0.02). Three of the 50 women (6%) taking VPA, and 0% of the 22 taking other antimanic medications, met criteria for PCOS (p = 0.20). Other reproductive and metabolic values outside the normal range across treatment groups included elevated 17 alpha-OH progesterone levels, luteinizing hormone: follicle-stimulating hormone ratios, homeostatic model assessment (HOMA) values, and low estrogen and dehydroepiandrosterone sulfate (DHEAS) levels. Preexisting menstrual abnormalities predicted higher levels of 17 alpha-OH progesterone, free testosterone, and estrone as well as development of new menstrual abnormalities. Body mass index (BMI) was significantly positively correlated with free testosterone levels and insulin resistance (HOMA) across all subjects, regardless of medication used.Rates of menstrual disturbances are high in women with bipolar disorder and, in many cases, precede the diagnosis and treatment for the disorder. Treatment with valproate additionally contributes significantly to the development of menstrual abnormalities and an increase in testosterone levels over time. A number of bipolar women, regardless of type of medication treatment received, have reproductive and metabolic hormonal abnormalities, yet the etiology of such abnormalities requires further study. Women with preexisting menstrual abnormalities may represent a group at risk for development of reproductive dysfunction while being treated for bipolar disorder.

Abstract

Perimenopause, the interval of irregular menstrual activity which directly precedes menopause, is characterized by widely fluctuating hormone levels amidst a large-scale decline in circulating estrogen. This phase in a woman's life is typically accompanied by physical discomforts including vasomotor symptoms, such as headaches, insomnia, and hot flushes, as well as genital atrophy. Not surprisingly, studies suggest a significant increase in mood lability for women during this time. While some evidence points toward an exacerbation of bipolar mood symptoms and an increase in schizophrenic psychosis during perimenopause, the majority of research conducted on perimenopausal mental disorders has focused on unipolar depression. Studies vary widely in methodology, definitions of menopausal status, and degrees of depression among subjects; however, the majority of findings indicate an increased susceptibility to depression during the perimenopausal transition. This greater susceptibility may be due to neuroendocrine effects of declining estrogen levels, the subjective experience of somatic symptoms resulting from this hormonal decline, and/or the more frequent occurrence of "exit" or "loss" events for women during this stage of life. At this time, more research is needed to address questions of prevalence, risk, and etiology for depression and other major mental disorders as related to the physiological and psychosocial changes associated with perimenopause.

Abstract

Supplementation of standard treatment with high-dose levothyroxine (L-T(4)) is a novel approach for treatment-refractory bipolar disorders. This study tested for effects on brain function associated with mood alterations in bipolar depressed patients receiving high-dose L-T(4) treatment adjunctive to ongoing medication (antidepressants and mood stabilizers). Regional activity and whole-brain analyses were assessed with positron emission tomography and [(18)F]fluorodeoxyglucose in 10 euthyroid depressed women with bipolar disorder, before and after 7 weeks of open-label adjunctive treatment with supraphysiological doses of L-T(4) (mean dose 320 microg/day). Corresponding measurements were acquired in an age-matched comparison group of 10 healthy women without L-T(4) treatment. The primary biological measures were relative regional activity (with relative brain radioactivity taken as a surrogate index of glucose metabolism) in preselected brain regions and neuroendocrine markers of thyroid function. Treatment-associated changes in regional activity (relative to global activity) were tested against clinical response. Before L-T(4) treatment, the patients exhibited significantly higher activity in the right subgenual cingulate cortex, left thalamus, medial temporal lobe (right amygdala, right hippocampus), right ventral striatum, and cerebellar vermis; and had lower relative activity in the middle frontal gyri bilaterally. Significant behavioral and cerebral metabolic effects accompanied changes in thyroid hormone status. L-T(4) improved mood (remission in seven patients; partial response in three); and decreased relative activity in the right subgenual cingulate cortex, left thalamus, right amygdala, right hippocampus, right dorsal and ventral striatum, and cerebellar vermis. The decrease in relative activity of the left thalamus, left amygdala, left hippocampus, and left ventral striatum was significantly correlated with reduction in depression scores. Results of the whole-brain analyses were generally consistent with the volume of interest results. We conclude that bipolar depressed patients have abnormal function in prefrontal and limbic brain areas. L-T(4) may improve mood by affecting circuits involving these areas, which have been previously implicated in affective disorders.

Abstract

The question of whether estrogen replacement therapy (ERT) is beneficial to cognitive functioning in postmenopausal women has become controversial in the past several years. Early studies suggested that ERT improved cognitive functioning and decreased the risk of Alzheimer's disease, but recent studies have failed to find any benefit. However, studies have varied in terms of the age of participants, the estrogen preparation used, whether progesterone is administered concurrently, and the study design. The present study used a randomized, placebo-controlled design and a transdermal estrogen preparation composed of 17-beta estradiol. A neuropsychological battery was administered at baseline and after completion of the 10-week trial, and test scores were grouped into four composite scores using psychometric techniques. Baseline to follow-up change was analyzed using multiple regression techniques. Results indicate that while little overall beneficial effect of estrogen was found, years since menopause was significantly related to change in executive functioning in the estrogen but not the placebo group, such that more recently postmenopausal women demonstrated greater positive change than older women. Body mass index, a gross estimate of circulating estrogen, was significantly positively related to change in attentional and psychomotor processes regardless of treatment group, and to a weaker extent, verbal memory, but only in the estrogen-treated group. These results suggest that reproductive events and levels of endogenous estrogen are related to the clinical response to ERT, but larger studies with longer follow-up periods are needed to determine the strength of these effects.

Abstract

To evaluate a localized two-dimensional correlated magnetic resonance spectroscopic (L-COSY) technique in patients with hepatic encephalopathy (HE) and healthy subjects, and to correlate the cerebral metabolite changes with neuropsychological (NP) test scores.Eighteen minimal hepatic encephalopathy (MHE) patients and 21 healthy controls have been investigated. A GE 1.5-T magnetic resonance (MR) scanner was used in combination with a body MR coil for transmission and a 3-inch surface coil for reception. A 27-mL voxel was localized by three slice-selective radio frequency (RF) pulses (90 degrees-180 degrees-90 degrees) in the anterior cingulate region. The total duration of each two-dimensional L-COSY spectrum was approximately 25 minutes. The NP battery included a total of 15 tests, which were grouped into six domains.MR spectroscopic results showed a statistically significant decrease in myo-inositol (mI) and choline (Ch) and an increase in glutamate/glutamine (Glx) in patients when compared to healthy controls. There was also an increase in taurine (Tau) in patients. The NP results indicated a significant correlation between motor function assessed by NP tests and mI ratios recorded using two-dimensional L-COSY.The study demonstrated the feasibility of evaluating the two-dimensional L-COSY sequence in a clinical environment. The results showed additional cerebral metabolites that can be measured with the technique in comparison to one-dimensional study.

Abstract

This prospective, longitudinal study investigated the frequency and pattern of mood changes between outpatients receiving usual care for bipolar disorder who were either taking or not taking antidepressants. Eighty patients with bipolar disorder self-reported mood and psychiatric medications daily for 3 months using a computerized system (ChronoRecord) and returned 8662 days of data. Of the total group of 80 patients, 47 took antidepressants; 33 did not. Patients taking antidepressants reported depression twice as frequently (29% of days vs. 13.8% of days). In both groups, two-thirds of all mood changes over a 1-, 2- and 3-day period were small, between -5 and 5 on a 100-point scale. No statistically significant difference was found in the frequency of large mood changes (>10 on a 100-point scale) or in switches between depression and mania (0.7% if not taking antidepressants vs. 0.9% if taking), independent of diagnosis of bipolar I or II. Eighty-nine percent of patients taking antidepressants were also taking mood stabilizers. In this naturalistic setting, no significant difference between the rate of switches to mania or rapid cycling was found between those taking and not taking antidepressants, regardless of diagnosis. The primary difference in pattern between the groups was the time spent in depressed or normal mood, with minor daily mood variations.

Abstract

Automating data collection from patients can improve data quality, enhance compliance, and decrease costs in longitudinal studies. About half of all households in industrialized countries now have a home computer.While we previously validated the ChronoRecord software for self-reporting mood on a home computer with patients who have bipolar disorder, this study further investigates whether this technology created a bias in the collected data.During the validation study, 80 of 96 (83%) patients returned 8662 days of data (mean, 114.7 +/- 32.3 SD days). The patients' demographics were compared with those of similar longitudinal studies in which patients used paper-based data collection tools. In addition, because demographic characteristics may influence attitudes toward technology, observer-rated scores on the Hamilton Depression Rating Scale and Young Mania Rating Scale were used to group patients by severity of illness, and the self-reported mood ratings were analyzed for evidence of bias from the patients' gender, ethnicity, diagnosis, age, disability status, or years of education. Analysis was performed using the 2-way analysis of variance and general linear model.The patients' demographic characteristics were very similar to those of patients with bipolar disorder who participated in comparable longitudinal studies using paper-based tools. After grouping the patients by severity of illness, none of the demographic variables had a significant effect on the patients' self-reported mood using the automated tool.The use of a computer does not seem to bias sample data. As with studies using paper-based self-reporting, results from studies of patients using ChronoRecord software on a home computer to report mood can be generalized.

Abstract

While the prevalence of bipolar disorder I is similar between men and women, the clinical course may differ. This study investigated if there are differences in the clinical presentation of bipolar disorder between the sexes.Mood patterns were documented using ChronoRecord software for self-reporting. Patients entered mood, medications, sleep, life events and menstrual data daily acquired over the period of three months. 8662 Days of data were received from 80 patients: 3483 days from 35 men and 5179 days from 45 women.The distribution of the time spent in mood categories differed between men and women (P<0.001). Men were depressed 17.0% of the time, euthymic 74.0% of the time and manic 5.6% of the time. Women were depressed 28.3% of the time, euthymic 64.2% of the time and manic 7.5% of the time. Over 80% of all reported symptoms for both sexes were mild. Women exhibited large mood fluctuations (greater than 10 in either direction on a 100-unit scale) more frequently than men. Most of the reproductive aged women (55%) reported significant mood changes across the menstrual cycle.The clinical course of bipolar disorder differed between the sexes. Women reported depression and large fluctuations in mood more frequently than men. Women also experienced mood changes across the menstrual cycle.

Abstract

This prospective study was designed to determine whether patients with prophylaxis-resistant affective disorders, receiving adjunctive maintenance therapy with supraphysiological doses of levothyroxine (L-T4), show evidence of accelerated bone loss compared to the reference population database.In 21 patients, bone mineral density (BMD) of the spine (lumbar vertebrae L1-L4) and femur (femoral neck, trochanter, and Ward's triangle) was measured by dual energy X-ray absorptiometry (DXA). BMD measurement was performed first after patients had been on thyroid-stimulating hormone (TSH)-suppressive therapy with L-T4 (mean dose=411 mcg/d) for an average of 16.4 months and again after 33.6 months of L-T4 (mean dose=416 mcg/d) therapy.There was no statistically significant difference between the actual percentage decline in bone mineral density and the expected percentage decline in any of the measured bone regions. In a stepwise linear regression analysis, age was identified as a predictor of percentage change in BMD. After controlling for age, the only other variable that showed a consistent trend was the dose of L-T4, with higher doses being positively correlated with the percentage decline of BMD.Relatively small sample size, no bone density assessment prior to treatment with L-T4, no patient control group with mood disorders who did not receive L-T4 treatment, and bone density follow-up intervals were variable.This study did not demonstrate evidence that long-term treatment of affectively ill patients with supraphysiological doses of L-T4 significantly accelerates loss of bone mineral density compared to the age-matched reference population. However, the decline of BMD in one individual patient underscores that caution is indicated and that regular assessment of BMD during longer-term supraphysiological thyroid hormone treatment is needed.

Abstract

To evaluate lamotrigine in a woman with a 30-year history of treatment-resistant menstrually-entrained rapid cycling bipolar II disorder with follicular phase depressive and luteal phase mood elevation symptoms.Lamotrigine was started at 5 mg/day and gradually increased up to 300 mg/day, while venlafaxine was tapered gradually and discontinued, and divalproex sodium 500 mg/day and levothyroxine 175 mcgm/day were continued. Daily self-reported mood ratings were obtained from the patient, using ChronoRecord software.As lamotrigine was increased gradually, mood cycle amplitude attenuated. There was notable decrease in the severity and duration of depressive symptoms specifically during the follicular phase of the menstrual cycle. At the time of submission of this paper, the subject had remained euthymic for a total of 12 months.This case suggests the potential utility of lamotrigine in treatment-resistant menstrually-related rapid cycling bipolar disorder, and raises the possibility that lamotrigine might be able to treat pathological entrainment of mood with the menstrual cycle. Both of these issues merit systematic assessment.

Abstract

This study prospectively followed women over the course of pregnancy to assess the impact of depression and/or antidepressant treatment on obstetrical outcome.Sixty-four outpatient women with an Axis I diagnosis of major depressive disorder or no psychiatric history were followed in each trimester of pregnancy with administration of the CES-D. A subset of the women with depression received treatment with fluoxetine during pregnancy. Subjects with a CES-D score greater than 16 at any time point were further assessed for the presence of an active major or minor depressive episode. Primary outcome variables included infant gestational age, birth weight, Apgar score, and admission to the neonatal intensive care unit.Analyzable data were available for 62 women. No significant differences were found in outcome variables between those women with exposure to medication and/or prenatal depressed mood and those women without a history of depression.In contrast to other studies, our study did not demonstrate an adverse effect of fluoxetine exposure per se on obstetrical outcome. In addition, we did not find a significant impact of depression during pregnancy on obstetrical outcome.

The relationship between polycystic ovary syndrome and antiepileptic drugs - A review of the evidenceJOURNAL OF CLINICAL PSYCHOPHARMACOLOGYRasgon, N.2004; 24 (3): 322-334

Abstract

Polycystic ovary syndrome (PCOS) is a serious endocrine disorder characterized by ovulatory dysfunction and hyperandrogenism that is thought to have a higher prevalence in women with epilepsy and perhaps bipolar disorder. Various theories have been offered to explain this higher prevalence of PCOS and other reproductive disorders in these patient populations, including the effects of the disease itself and of antiepileptic drugs, especially valproate, which may directly cause PCOS or indirectly lead to the disorder by causing weight gain that triggers insulin resistance, increased testosterone levels, and other reproductive abnormalities. A prospective, longitudinal study with larger cohorts in newly diagnosed women with epilepsy or bipolar disorder is needed to definitively characterize the relationship between antiepileptic drugs and PCOS. Until data from such a study are available, physicians need to be aware that there is a possibility of developing symptoms of PCOS in women of reproductive age who are treated with antiepileptic drugs. Despite this concern, the choice of antiepileptic drug for women with epilepsy or bipolar disorder should be based on the most effective agent for controlling neurologic symptoms.

Abstract

There are obvious gaps in research surrounding issues specific to women who suffer from bipolar disorder, including gender differences and their implications for management, the impact of the reproductive cycle, and evidence based treatment guidelines for pregnancy and the postpartum period. Gender differences have not been reported for the prevalence of bipolar disorder; however, women are more likely to experience rapid cycling, mixed mania, and antidepressant-induced manias. This may affect response to treatment, which has been found, in some cases, to differ in men and women. In addition, side effects in response to treatments may well differ in men and women, especially with regard to lithium and valproate prescription. The course of bipolar disorder in women may be influenced by the menstrual cycle, pregnancy, the postpartum period, and menopause, although many issues require further clarification. Treatment of bipolar disorder during pregnancy and the postmenopausal period requires careful consideration, as does treatment during the childbearing years, as some mood stabilizers influence the metabolism of oral contraceptives. This review article has attempted to evaluate existing literature regarding women with bipolar disorder in a comprehensive and critical way, and to consolidate into a single source the gender-specific aspects of the disorder that may have treatment implications for women.

Abstract

Longitudinal studies are an optimal approach to investigating the highly variable course and outcome associated with bipolar disorder, but are expensive and often have missing data. This study validates patient self-reported mood ratings using a home computer-based system (ChronoRecord) with clinician mood ratings on the Hamilton Depression Rating scale (HAMD) and Young Mania Rating scale (YMRS), and investigates the patient acceptance of the technology.After brief training, outpatients with bipolar disorder were given the software version of an established paper based self-reporting form (ChronoSheet) to install on a home computer. Every day for 3 months, patients entered mood, medications, sleep, life events, and menstrual data. Weight was entered weekly.Eighty of 96 (83%) patients returned 8662 days of data. The mean days of data returned was 114.7 +/- 32.3 SD The mean percentage of days missing for mood data was 6.1% +/- 9.3 SD, equivalent to missing 7.3 day of the 114.7 days. Self-reported ratings were strongly correlated with clinician HAMD ratings (-0.683, p < 0.001).This study demonstrates concurrent validity between ChronoRecord and HAMD. Patients with bipolar disorder showed high acceptance of a computer-based system for self-reporting of daily data. Automation of data collection can reduce missing data and eliminate errors associated with data entry. This technology also enables on-going feedback for both patient and researcher during a long-term study.

Abstract

Affective disorders (ad) and Alzheimer's disease (AD) have been associated for almost a century, and various neurophysiologic factors have been implicated as common biologic markers. Yet, links between ad and AD still await elucidation. We propose that insulin resistance (IR) is one of the missing links between ad and AD. IR with hyperinsulinemia and subsequent impairment of glucose metabolism especially in ad patients may promote neurodegeneration and facilitate the onset of AD. According to our hypothesis, IR may persist even into ad remission in some patients. Persistent regional hypometabolism and vascular changes resulting from long-standing IR may lead to currently irreversible structural changes. Evidence in support of the hypothesis is reviewed and clinical implications suggested.

Abstract

Longitudinal studies are the optimal approach when investigating the highly variable course of bipolar disorder, but such studies are expensive, prone to reporting errors and to missing data. Automation of data collection may reduce such errors and improve data quality. The ChronoRecord, validated software that patients can install on a home computer to report mood, medications, sleep, life events, weight and menstrual data, has been designed to achieve such automation. In the trial of the ChronoRecord reported here, 80 of 96 (83 %) patients with bipolar disorder showed high acceptance of this computer-based system for self-report, entering daily recordings for a period of 3-months. This new technology, in addition to providing an accurate longitudinal record for research purposes, also facilitates on-going patient feedback and accurate study monitoring.

Abstract

The efficacy resulting from adjunctive use of supraphysiological doses of levothyroxine has emerged as a promising approach to therapy and prophylaxis for refractory mood disorders. Most patients with mood disorders who receive treatment with supraphysiological doses of levothyroxine have normal peripheral thyroid hormone levels, and also respond differently to the hormone and tolerate it better than healthy individuals and patients with primary thyroid diseases. Progress in molecular and functional brain imaging techniques has provided a new understanding of these phenomena, illuminating the relationship between thyroid function, mood modulation and behavior. Thyroid hormones are widely distributed in the brain and have a multitude of effects on the central nervous system. Notably many of the limbic system structures where thyroid hormone receptors are prevalent have been implicated in the pathogenesis of mood disorders. The influence of the thyroid system on neurotransmitters (particularly serotonin and norepinephrine), which putatively play a major role in the regulation of mood and behavior, may contribute to the mechanisms of mood modulation. Recent functional brain imaging studies using positron emission tomography (PET) with [ (18)F]-fluorodeoxyglucose demonstrated that thyroid hormone treatment with levothyroxine affects regional brain metabolism in patients with hypothyroidism and bipolar disorder. Theses studies confirm that thyroid hormones are active in modulating metabolic function in the mature adult brain, and provide intriging neuroanatomic clues that may guide future research.

Abstract

The aim of this study was to develop a mathematical model of the hypothalamo-pituitary-gonadal axis that would reflect available data in humans.A model of hormonal relationships at the early follicular and midluteal phases of the human menstrual cycle is proposed.Two distinct temporal patterns of oscillatory behavior have been demonstrated for both pituitary and gonadal steroids in the early follicular phase: first, rapid oscillations in gonadotropin releasing hormone, follicle stimulating hormone and luteinizing hormone (Q approximate to 1 hour) that were an immediate consequence of the programmed equations. Second, there were slower, undulating, emergent rhythms in luteinizing hormone and follicle stimulating hormone, and also in estrogen, having oscillatory periods of 2-12 hours. There was also a longer-period (Q2-3 days) emergent rhythm in progesterone. In the mid-luteal phase, estrogen and progesterone rhythms were correlated, and all hormones showed an approximately 6-hour periodicity.To our knowledge, the oscillatory behavior of peripheral sex steroids in the follicular phase has not been previously noted.

Abstract

We assessed the prevalence of mood disturbance among women with prospectively documented polycystic ovary syndrome (PCOS).Thirty-two women with PCOS completed the Center for Epidemiological Studies-Depression Rating Scale (CES-D). Clinical and biochemical characteristics were assessed.Sixteen women had CES-D scores indicative of depression. Depression was associated with greater insulin resistance (P=0.02) and higher body mass index (P=0.05). Women receiving oral contraceptives for the treatment of PCOS were less depressed than patients not receiving treatment (P=0.03).Possible selection bias, use of a screening tool alone without further diagnostic evaluation of depression, small samples size and lack of direct comparison with an age matched control group, should be considered in interpretation of these results.Findings suggest a high prevalence of depression among women with PCOS, and an association between depression and PCOS markers.

Abstract

A relationship between affective symptoms and menstrual cycle in women with bipolar disorder (BPD) has been suggested. This study investigates the influence of the menstrual cycle on mood in women with BPD who are taking medication, but not selected for menstrual abnormalities.Data from women with BPD (n = 17) consecutively enrolled into a ChronoRecord validation study were included in the current analysis. All women received medication for BPD, in addition, 35% received oral contraceptives (OC). Participants entered mood, menstrual data, psychiatric medications, and life events daily for a 3-month period using a computerized version (ChronoRecord) of an established paper based form for self-reporting (ChronoSheet).The majority of women treated for BPD (65%) reported significant mood changes across the menstrual cycle. Long menstrual cycle was present in 59% of subjects, including those taking OC.Women with BPD taking medication report a high rate of long menstrual cycles, and significant mood changes in relation to menstrual cycle phase.

Abstract

Various mood and anxiety disorders are more prevalent in reproductive-aged women, and appear to be linked to hormonal and reproductive events. Premenstrual affective disorders consist of premenstrual syndrome, premenstrual dysphoric disorder, and premenstrual exacerbation of mood or anxiety disorders. Postpartum affective disorders can range from postpartum "blues" to postpartum depression with or without psychosis, and also include anxiety disorders, such as panic disorder, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder. In perimenopausal women, the vulnerability to mood and anxiety disorders is increased. All of these disorders share risk factors, and have etiologic features in common, such as exposure to the rise and fall of ovarian sex steroids. The following is a review of these syndromes and their etiology, diagnosis, and treatment.

Abstract

Previous studies have suggested sex differences in mood and cognition and that estrogen effects may partially explain such differences. In this study, we explore sex differences for a range of mood symptoms and for neuropsychological performance in men and postmenopausal women and assess the potential influence of estrogen on these measures.Cross-sectional study of men and women examining mood, neuropsychological test data, and estrogen replacement therapy (ERT) use.Outpatient study at an urban teaching hospital with subjects recruited from the community.All subjects (N = 96) were between the ages of 57 and 75 and included 31 women using ERT, 16 non-ERT users, and 49 men. Subjects did not have major depression and were nondemented.The three groups were compared according to profile of mood states and neuropsychological performance, and statistical analyses were controlled for socioeconomic status, age, and education level.Female ERT users were less depressed and less angry and performed better on measures of verbal fluency and working memory than the other subject groups.Postmenopausal estrogen use is associated with better mood and cognitive performance on tasks of fluency and working memory. These results suggest that estrogen should be examined as a potentially critical variable influencing late-life sex differences in mood and cognition.

Abstract

We present the case of a young woman with treatment-resistant major depression, who presented to the Mood Disorders Clinic with a Hamilton Psychiatric Rating Scale for Depression (HAM-D-21) score of 28, after a year-long treatment with Effexor-XR. The patient also had untreated Polycystic Ovarian Syndrome (PCOS). The resolution of her depressive symptoms resulted from the treatment for PCOS with metformin and spironolactone. The patient remained euthymic 5 months after discontinuation of the antidepressant while continuing therapy for PCOS. We briefly overview of the pertinent literature of the pathophysiology of PCOS and affective disorders, highlighting an overlap in phenotypical presentations between these two disorders. Dysregulation of the hypothalamo-pituitary axis and various end organ systems are implicated in both PCOS and affective disorders. As such, several clinical and biochemical markers are common to both disorders, namely insulin resistance, obesity, and hyperandrogenism. In addition, these metabolic abnormalities are interrelated, causing women with PCOS or affective disorders to get caught in a "vicious cycle" of hormonal dysregulation. The case report presented here illustrates how treatment of symptoms such as insulin resistance and hyperandrogenism can lead to remission of major depressive disorder and PCOS. We suggest that through treatment of underlying metabolic defects, both the mood of the patient and the metabolic condition of PCOS can be assisted.

Abstract

Increased vulnerability to mood disorders has been reported during perimenopause. Fluctuating estrogen levels accompany the perimenopausal transition. Thus, estrogen replacement therapy (ERT) has been proposed as a potentially effective treatment for mood disorders occurring during perimenopause.We examined the efficacy of ERT in the treatment of depression in 16 perimenopausal women with DSM-IV-defined major depressive disorder who were participating in the Mood Disorders Research Program at the Department of Psychiatry of the University of California, Los Angeles. Ten antidepressant- and ERT-naive women received ERT alone. Six women who were nonresponders or partial responders to an antidepressant received ERT in addition to existing treatment with fluoxetine. The Hamilton Rating Scale for Depression (HAM-D) was administered to all patients at baseline and weekly thereafter during the 8-week open-protocol trial. Partial response was operationalized as a final HAM-D score < or = 50% of the baseline score. Remission was defined as a final HAM-D score < or = 7.All patients exhibited clinical improvement as measured by HAM-D scores after the first week of treatment. Of the 10 perimenopausal depressed women receiving ERT alone, 6 remitted, 3 partially responded to treatment, and 1 did not respond by the end of the trial. Of the 6 women receiving antidepressant treatment with ERT, 1 patient remitted and 5 had a partial response by the end of the trial.This small study suggests that for some antidepressant-naive perimenopausal women with clinical depression, ERT may have antidepressant efficacy. In depressed women who have minimal response to a selective serotonin reuptake inhibitor, ERT may augment response. Further controlled trials are needed.

Abstract

To evaluate the circulating concentrations of the neuroactive steroids in response to an i.v. L-tryptophan (L-TP) challenge across the menstrual cycle in women with premenstrual syndrome (PMS) and in controls.An i.v. L-TP challenge was administered eight times during 1 month to five women with prospectively documented PMS and five age- and body mass-matched controls. Progesterone, allopregnanolone pregnenolone and 3alpha-5alpha-tetrahydrocorticosterone were assessed 15 and 0 min before, and at 30, 60 and 90 min after the challenge, across the menstrual cycle.In response to L-TP challenge, only allopregnanolone concentrations were significantly increased across the cycle and this increase was of a greater magnitude in women with PMS. Pregnenolone and 3alpha-5alpha-tetrahydrocorticosterone concentrations were not affected in women with PMS or controls after L-TP challenge.The data provide evidence for possible interaction between the serotonergic system and the neuroactive steroid, allopregnanolone. Women with PMS demonstrated a more significant increase in allopregnanolone concentrations in response to L-TP challenge, which could be due to an initial low basal serotonergic tone in the luteal phase in the PMS group.

Abstract

Because estrogen may influence brain blood flow and metabolism in older adults, we used positron emission tomography to evaluate cerebral glucose metabolic change in post-menopausal women and men. Women estrogen users (n=4), women non-users (n=8) and men (n=10) were scanned at baseline and two years later. Analyses focused on glucose metabolism in lateral temporal, inferior parietal and posterior cingulate brain regions, previously reported to decline in non-demented older persons. No metabolic differences in cerebral regions of interest were found among groups at baseline. At follow-up, women estrogen users showed significantly increased glucose metabolism in the lateral temporal region, whereas women non-users and men exhibited no significant metabolic change in this region. These findings suggest that estrogen use may protect against regional cerebral metabolic decline in postmenopausal women.

Abstract

Proton magnetic resonance spectroscopy (1H-MRS) was used to assess neurochemical brain changes across the menstrual cycle in five women with premenstrual dysphoric disorder (PMDD) and six control subjects. Women with PMDD and control subjects were scanned on days 8 and 26 within one menstrual cycle (i.e. at times of complete absence and height of PMDD symptoms, respectively). The point resolved spectroscopic sequence (PRESS) was used to localize a voxel of 8 ml in the medial frontal gray matter and in the occipito-parietal white matter. The ratio of N-acetyl-aspartate to creatine in the region of the medial prefrontal cortex and the cingulate gyrus declined significantly from the follicular to the luteal phase in both groups of subjects. The menstrual phase-dependent significant increase in the ratio of choline to creatine was observed in the parietal white matter. The myo-inositol/creatine ratio exhibited a trend toward higher levels in the PMDD patients in the luteal phase of the menstrual cycle. Differences between PMDD and control subjects were not statistically significant. Menstrual cycle phase-dependent changes in ovarian hormonal concentrations may influence the neurochemistry of brain activity in premenopausal women.

Abstract

The major known genetic risk for Alzheimer's disease (AD), apolipoprotein E-4 (APOE-4), is associated with lowered parietal, temporal, and posterior cingulate cerebral glucose metabolism in patients with a clinical diagnosis of AD. To determine cognitive and metabolic decline patterns according to genetic risk, we investigated cerebral metabolic rates by using positron emission tomography in middle-aged and older nondemented persons with normal memory performance. A single copy of the APOE-4 allele was associated with lowered inferior parietal, lateral temporal, and posterior cingulate metabolism, which predicted cognitive decline after 2 years of longitudinal follow-up. For the 20 nondemented subjects followed longitudinally, memory performance scores did not decline significantly, but cortical metabolic rates did. In APOE-4 carriers, a 4% left posterior cingulate metabolic decline was observed, and inferior parietal and lateral temporal regions demonstrated the greatest magnitude (5%) of metabolic decline after 2 years. These results indicate that the combination of cerebral metabolic rates and genetic risk factors provides a means for preclinical AD detection that will assist in response monitoring during experimental treatments.

Abstract

In patients with epilepsy, polycystic ovary (PCO) syndrome has been reported to be associated with the use of the anticonvulsant divalproex sodium. Whether PCO syndrome is associated with divalproex use in patients with bipolar disorder has not previously been explored.Twenty-two female outpatients with a DSM-IV diagnosis of bipolar disorder who were between the ages of 18 and 45 years (inclusive) and who were taking lithium and/or divalproex (10, divalproex monotherapy; 10, lithium monotherapy; 2, divalproex/lithium combination therapy) were evaluated. Patients completed questionnaires about their medical, psychiatric, and reproductive health histories, and body mass indices were calculated. In the early follicular phase of their menstrual cycle, women were examined for hirsutism, given a pelvic ultrasound, and/or assessed for changes in laboratory values such as serum levels of testosterone, free testosterone, estradiol, estrone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, luteinizing hormone, follicle-stimulating hormone, and 17-OH progesterone.All 10 patients on lithium monotherapy, 6 of 10 patients on divalproex monotherapy, and both of the patients on divalproex/lithium combination therapy reported some type of menstrual dysfunction, which, in 4 cases, had preceded the diagnosis of bipolar disorder. Hirsutism was not common in any group, but obesity was prominent in all groups. Ovarian ultrasound revealed an increased number of ovarian follicles in 1 patient taking lithium and in none of the patients taking divalproex. Hormonal screening did not indicate PCO-like changes in any patient.In this pilot study of bipolar patients, PCO-like changes were not seen in women receiving divalproex or lithium. However, independent of therapeutic agent used, the bipolar women in this study reported high rates of menstrual disturbances, suggesting that the hypothalamic-pituitary-gonadal axis may be compromised in some women with bipolar disorder.

Abstract

To evaluate the neuroendocrine responses to an intravenous L-tryptophan challenge across the menstrual cycle in women with premenstrual syndrome (PMS) and controls.Controlled clinical study.The Clinical Research Center of an academic research environment.Women with PMS and healthy volunteers.An intravenous L-tryptophan challenge was administered two times a week during 1 month to five subjects with prospectively documented PMS and five age- and body mass-matched controls.Whole-blood serotonin, cortisol, and prolactin levels were assessed at the baseline and at 30, 50, 60, 70, 80, and 90 minutes after the challenge.Whole-blood serotonin response to the L-tryptophan challenge was blunted in the luteal phase of the menstrual cycle in subjects with PMS compared with controls. Cortisol levels differed between groups and cycle phases only at the baseline, with higher baseline cortisol levels during the luteal phase in women with PMS, whereas baseline and postchallenge prolactin levels did not differ between groups.The present results support previously reported findings of alterations in tryptophan handling in women with PMS. The elevated baseline luteal phase cortisol concentrations in subjects with PMS warrants further investigation.

Abstract

This review describes the biological changes occurring in perimenopause and analyzes epidemiological studies that shed light on the relationship between perimenopause and mood. The role of estrogen as a treatment for depressive symptoms is also examined. We found that a positive association may exist between depressive symptoms and the perimenopause, and that a prior history of depression may be associated with such symptoms. In most of the studies reviewed, the use of estrogen in replacement doses appears to improve depressive symptoms in perimenopausal patients who do not have major depression. We suggest an approach to the treatment of middle-aged women presenting with such symptoms. No careful study of the incidence of DSM-IV major depression associated with perimenopause has been done, and the efficacy of estrogen as a primary or adjunctive treatment for the disorder during perimenopause is unclear.

Abstract

This paper describes a previously sufficiently functioning 57 year old man who presented with a recent onset of frontal behaviour. Partial agenesis of corpus callosum was an incidental finding on a computerized tomography scan. The EEG was within normal limits and neuropsychological testing did not reveal any interhemispheric disconnection. A SPECT-Scan revealed bilateral hypoperfusion, consistent with Alzheimer's dementia. Normal functioning up to 50 years of age and a later manifestation of Alzheimer's disease along with agenesis of carpus callosum is of clinical interest as such an association has not been published.

Abstract

In an attempt to clarify the nature of analgesic effect of alpha-tocopherol, the influence of alpha-tocopherol on the levels of endogenic opioids was studied in the experiments in vitro. Main changes of the level of adenohypophyseal (tissue) beta-endorphins and in the incubation media were evaluated as well as the involvement of the endogenous opioid system in the analgesic effect of alpha-tocopherol.

Abstract

Stress is shown to induce at first the generalized inhibition of lipid peroxidation (LPO), and then the activation of LPO. In brain and blood serum of rats subjected to continuous footshock as well as to restraint stress LPO products decreased and superoxide scavenging activity increased during the initial period of stress, after 1 hour of footshock LPO indices nearly reached normal values, and after 2 hours of footshock the accumulation of LPO products and decrease of superoxide scavenging activity were seen. LPO inhibition was accompanied by accumulation of easy oxidizable brain phospholipids and by depletion of brain cholesterol, during LPO activation brain cholesterol content and cholesterol-phospholipid ratio increased. The content of LPO products--fluorescent Schiff bases in blood plasma of women suffering from algomenorrhea at first decreased (O-12 h) and then dramatically increased (12-24 h) after a onset of pain at the beginning of menstruation. The data suggest that the stage of LPO inhibition precedes its activation during stress.

Abstract

Beta-endorphin-like immunoreactivity was studied in 7 patients with algomenorrhea during pain attack and 15 minutes after alpha-tocopherol administration with a therapeutic aim (till the analgetic effect was reached). There was an increase in beta-endorphin-like immunoreactivity after alpha-tocopherol administration. Naloxone administration to 9 patients with algomenorrhea of various etiology resumed the pain. The effect of alpha-tocopherol application for pain relief depended on the pathogenesis of algomenorrhea. At the same time naloxone administration failed to resume the pain in patients, in whom alpha-tocopherol had a strong analgetic effect. It is assumed that the endogenous opioid system participates in alpha-tocopherol effect on pain relief in patients with algomenorrhea.